Acute myeloid leukemia, myeloid leukemia, AML - symptoms, treatment and life prognosis for patients. Megakaryoblastic leukemia

UDC 616.411-003.972

E.Z. GABBASOVA,AND. S. SHERIAZDAN, G.A. SABYRBAEVA,

M.K. ZHUMAKHANOVA,

Kazakh national medical University them. S.D. Asfendiyarova

Department of Internship and Residency in Therapy No. 3

This article presents a clinical case of a rare variant acute leukemia– megakaryocytic. The clinical picture, morphological examination data andAndimmunophenotyping bone marrow. Features of the disease in the presented observation were the presence of thrombophilic episodes and unfavorable outcome.

Keywords: rare variant, acute leukemia, acute megakaryocytic leukemia, M7, clinical case.

Acute megakaryocytic leukemia(AML, AML M7, according to FAB classification) - a variant of acute myeloid leukemia, in which blast cells, which form the basis of the disease, are mainly represented megakaryoblasts(these are the precursor cells of megakaryocytes, from which, in turn, platelets are formed).

AML is a very rare variant of acute myeloid leukemia. Its exact proportion among all cases of acute myeloid leukemia, according to various estimates, is 3-10% in children (most often younger age and with Down's disease), and in adults only 1-2%. The age distribution of AML has two peaks: one among young children (up to 3 years), the other among older adults.

AML is characterized by the presence in the bone marrow and blood of megakaryoblasts (cells with a blastic but hyperchromic nucleus, narrow cytoplasm with filamentous outgrowths), as well as undifferentiated blasts. Often, ugly megakaryocytes and fragments of their nuclei are found in the blood and bone marrow. Thrombocytosis is characteristic (more than 100 - 104 in 1 μl), but thrombocytopenia may also be present. Immunophenotype of the pathological population: HLADR-/, CD33/, CD34, CD41, CD61. AML is difficult to treat, so the prognosis is usually unfavorable.

Considering the rarity of this variant of leukemia and the difficulties of its differential diagnosis, it seems appropriate to us to present our own observation of acute megakaryocytic leukemia.

Clinical observation

Patient M., 55 years old, in August 2011 was hospitalized in the hematology department of City Clinical Hospital No. 7 in Almaty. From the anamnesis it is known that since June of the same year, he was periodically bothered by nosebleeds, pain in the left hypochondrium, and began to notice increasing weakness, sweating, and weight loss. Subsequently, the patient was observed for thromboembolism pulmonary artery, due to which he was hospitalized in the hospital. During the examination: the hemogram revealed severe normochromic anemia, leukocytosis up to 62 thousand with neutrophilia, hyperthrombocytosis up to 1912x10 9 l, ESR-65 mm/hour; in the coagulogram: hypocoagulation, hyperfibrinogenemia, thrombinemia. After conservative treatment and stabilization of the general condition, the patient was referred for further examination and treatment to a hematologist.

Status on admission: severe condition, Karnofsky index 70%. The skin is pale, hemorrhagic ecchymoses at the injection sites. Asthenic, low nutrition. Zev is calm. Peripheral lymph nodes are not enlarged. T-36.6S.

From the respiratory system: rib cage normal shape, percussion - clear pulmonary sound. On auscultation, weakened vesicular breathing, silent fine rales in the lower parts. ChD-24 per min. Heart sounds are muffled, the rhythm is correct. Blood pressure 120/70mmHg. Pulse-83 per minute. The tongue is moist and clean. The abdomen is soft and painless. Liver +3 cm from under the edge of the costal arch, soft-elastic consistency, painless. The spleen is not palpable. The chair is decorated, in a regular color. Urination is free and painless. Diuresis is adequate. The effleurage symptom is negative on both sides. There is no peripheral edema.

Peripheral blood analysis: hemoglobin -80 g/l, erythrocytes - 2.5x10 12 /l, platelets - 2000x10 9 /l, leukocytes - 72x10 9 /l, blastemia - 12%.

Morphological examination of the bone marrow: blasts make up 60.6%. Blast cells are polymorphic. Cells vary in size, and both macro- and mesoforms are found. The outlines of the cells are irregular. The nuclear-cytoplasmic ratio is moderate. The nucleus is round, with a fine mesh chromatin structure. The kernel structure is rough. The cytoplasm is basophilic, granular, and has the appearance of a narrow rim. The contours of the cells are uneven, with processes of the cytoplasm and the formation of “blue” plates. There are many megakaryocytes of an ugly shape and fragments of their nuclei in the field of view. When assessing the residual germs of hematopoiesis, attention is drawn to the pronounced dysplasia of elements of the granulocytic and erythroid series.

Immunophenotyping of bone marrow cells revealed a pathological population of progenitor cells with a phenotype characteristic of megakaryocytic leukemia: HLADR-/, CD33/, CD34, CD41.

Based on the above studies, according to the FAB classification criteria, a diagnosis of AML M-7, a megakaryocytic variant of acute leukemia, was established. Two standard courses of cytostatic therapy were carried out according to the “7+3” scheme (cytosar, rubomycin). Soon the patient developed acute thrombosis of the inferior vena cava and was surgical treatment: through the skin, through the jugular implantation of a permanent cava filter into the infrarenal part of the inferior vena cava.

There was no expected effect from the PCT courses. Symptoms of intoxication increased. The last hospitalization for emergency reasons with severe symptoms of tumor intoxication, multiple organ failure, leukemic infiltration of internal organs. The patient died 6 months after diagnosis from acute cardiovascular failure due to progression of the underlying disease. The autopsy was not performed according to the wishes of the relatives for religious reasons.

Thus, given the general rarity of acute megakaryocytic leukemia in adult patients, the presented observation is interesting in that it concerns a patient who, at the age of 55 years, was diagnosed with acute megakaryocytic leukemia, against the background of which episodes of thrombophilic conditions were repeatedly noted.

BIBLIOGRAPHY

1 Jaffe E. S., Harris N. L., Stein H., Vardiman J. W. (eds.). World Health Organization Classification of Tumors. //Pathology and Genetics of Tumors of haematopoietic and lymphoid tissues. Lyon: IARC, 2001.

2 Lowenberg B., Downing J. R., Burnett A. Acute myeloid leukemia // N. Engl. J. Med. – 1999. – R. 341.

3 Duchayne E., Fenneteau O., Pages M. P. et al. Acute megakaryoblastic leukaemia: a national clinical and biological study of 53 adult and childhood cases by the Groupe Francais d’Haematologie Cellulaire (GFHC) // Leuk. Lymphoma. -2003.- 44(1).

4 Abdulkadyrov K.M. Hematology // Newest reference book. – St. Petersburg, 2004

E.Z. GABBASOVA, Zh.S. SHERIYAZDAN, G.A. SABYRBAEVA,

Zh.I. BORANBAEVA, U.N. ZHIENBEKOVA,M.K. ZHUMAKHANOVA,

J.S. KALBASOVA, A.A. SEYTKABYLOVA

ZHEDEL MEGAKARYOCYTELS LEUKEMIA – LEUKOZDYҢ SIREK NUSKASY (OZINDIK BAKYLAU)

Tү yin: Atalgan makalada zhedel leukozdyn sirek nuskasy – megakaryocytes leukozdyn klinikalyk zhagdayy korsetilgen. Klinikalyk korіnіsі, morfologichesk zertteu zhane suyek kemigіn immunophenotype u malimetteri sipattalgan. Korsetilgen baqylauda was aurudyn ereksheligi thrombophilialyk episodetar zhane kolaysyz natizhe bolyp tabylady.

Tү withө zder: sirek nuska, zhedel leukemia, zhedel megakaryocytarly leukemia, M7, klinikalyk zhagday.

E.Z. GABBASSOVA, ZH. S. SHERIYAZDAN, G.A. SABYRBAYEVA,

J.I. BORANBAEVA, U.N. ZHIENBEKOVA, M.K. ZHUMAHANOVA,

ZH.S. KALBASOVA,A.A. SEYTKABYLOVA

ACUTE MEGAKARYOCYTIC LEUKEMIA – A RARE VARIANT OF LEUKEMIA (OWN OBSERVATION)

Resume: This article presents a case report of a rare variant of acute leukemia - megakaryocyte. We describe the clinical picture, these morphological studies and immunophenotyping bone marrow. Feature of the disease in the present observations were the presence of thrombophilic episodes and poor outcome.

Keywords: rare variant, acute leukemia, acute megakaryocytic leukemia, M7, clinical case.

Megakaryoblastic leukemia(M7) is a rare variant of leukemia that is combined with bone marrow fibrosis (acute myelosclerosis). Acute megakaryoblastic leukemia is characterized by the presence in the blood and bone marrow of megakaryoblasts - cells with a hyperchromatic (excessively stained) nucleus, narrow cytoplasm with thread-like outgrowths, as well as undifferentiated blasts. Often, ugly megakaryocytes, as well as fragments of their nuclei, are observed in the blood and bone marrow. Acute megakaryoblastic leukemia is the most common type of acute leukemia in children with Down syndrome. Megakaryoblastic leukemia is often combined with bone marrow fibrosis (for example, acute myelosclerosis). It is difficult to treat and therefore the prognosis is usually unfavorable. The megakaryoblast essence of cells is determined not only using electron microscopy in combination with a cytochemical examination for peroxidase, but also using antiplatelet antisera, which reveal specific markers on the cells of this series.

treatment

Myelofibrosis and low levels of infrequently dividing blasts interfere with cytotoxic therapy, which is necessary due to profound cytopenia. Predominantly cytostatic therapy does not bring the desired effect and even complicates cytopenia. The most effective way Treatment of acute megakaryoblastic leukemia with manifest myelofibrosis is considered to be a bone marrow transplant.

symptoms

Clinical signs are the same for all types of acute leukemia and can be quite polymorphic. The onset of the disease can be sudden or gradual. There is no characteristic onset or specific clinical signs for them. Just a thorough analysis clinical picture makes it possible to recognize a more serious disease hiding under the guise of a “banal” disease. A combination of symptoms of bone marrow failure and symptoms of a specific lesion is typical. Due to leukemic infiltration of the mucous membranes of the oral cavity and tonsil tissue, necrotic gingivitis occurs, necrotizing tonsillitis. Sometimes a secondary infection is added and sepsis is formed, which can lead to death. The symptoms of acute megakaryoblastic leukemia are mostly devoid of specific features. As a result of the disease, suppression of normal myelopoiesis and other signs of the terminal stage are noted. In some cases, acute megakaryoblastic leukemia can have the clinical and hematological picture of acute low-grade leukemia, and the bone marrow histology resembles the picture of myelofibrosis. This form of megakaryoblastic leukemia is characterized by a low content of blast cells in the blood and bone marrow, a polymorphic cellular structure of the bone marrow, often manifested by megakaryocytosis in the bone marrow and diffuse myelofibrosis, and occasionally osteomyelosclerosis. Myelofibrosis usually makes it impossible to perform a bone marrow puncture throughout the course of the disease. Cytochemical and cytological analysis blast cells that enter the blood, for the most part, do not identify in them specific signs of belonging to any germ of hematopoiesis.

Acute myeloid leukemia (AML or myeloid leukemia, as may be indicated in the patient's medical history) is one of the many types of cancer of the blood that provokes disturbances in normal hematopoiesis. In this disease, embryonic hematopoietic cells, which have acquired the ability to further function in the form of leukocytes, for some reason stop in their development. The occurrence of acute myeloid leukemia is very dangerous due to irreversible changes in the blood and high mortality.

Emergence pathological condition has a direct connection with the occurrence of the mutation process at one of the sites of hematopoiesis (blood formation) occurring in the bone marrow. Acute myeloid leukemia, an oncology that patients do not quite correctly call “,” because cancerous structures are localized mainly in epithelial tissues, affects granulocytes, which are a subgroup of leukocytes containing large nuclei and cytoplasm that has a granular structure. This type of white blood cells, due to exposure to a damaging factor, loses the ability to mature and naturally self-destruct after a certain time, inherent normal elements blood.

The result of the pathological process is:

• entry into the bloodstream of immature cells, blasts, which do not carry any functional significance;
• active division of these elements, leading to their rapid growth and displacement of healthy white blood cells;
• decline and total loss body protective functions, as a result of which he becomes vulnerable to any infectious lesion.

The increase in the number of blasts in the bloodstream has a very high speed, so a short period of time passes from the onset of acute myeloid leukemia. In some cases, a few weeks are enough from the appearance of the first mutated blood cell until the moment when acute myeloid leukemia becomes incurable. The high mortality rate from this disease is associated with the irreversibility of the process of changing the structure of cells, its high speed and the emergence of resistance to therapeutic effects in them.

Acute myeloid leukemia in children

This disease is relatively rare in children, but some children are still at risk of its occurrence. Acute myeloid leukemia is diagnosed mainly in children under three years of age, with equal frequency in boys and girls.

This trend indicates that a genetic factor plays a major role in the occurrence of pathologies of the hematopoietic organs:

• In children under 3 years of age, all hereditary pathologies that can lead to the development of oncological damage to the hematopoietic elements are clearly manifested.
• at an older age, from three to seven years, their influence is significantly reduced and at the same time there are no acquired pathological processes, which can lead to oncological damage to the myeloid lineage.

Worth knowing! When a child reaches the age of seven, his risk of developing an acute form of myeloid leukemia increases again. Most often, this disease is diagnosed in children growing up with parents who smoke and drink. Also, acute myeloid leukemia develops in children living in poor environmental conditions (next to large industrial enterprises or nuclear power plants).

Classification of oncological blood pathology

To more accurately identify the type of cancer, which helps to choose the optimal course of therapy, acute myeloid leukemia is usually classified. The division of the pathological condition into types occurs in accordance with the most significant signs of the developing disease from a prognostic point of view.

The generally accepted WHO classification for this disease includes 7 variants of the course of AML:

1. Myeloblastic leukemia, which develops in the complete absence of signs of maturation in blast cells.
2. (AML) with incomplete maturity of the cellular elements that gave rise to it.
3. Promyeloblastic (promyleocytic) leukemia. In this form of pathology, promyelocytes, the cells that precede the appearance of granulocytes, undergo mutations.
4. . Blast and epithelial cells predominate in the bloodstream. The level of white blood cells that have begun to mature and fully mature does not reach 10% of the total number of leukocytes.
5. Monoblastic. The bulk of the blood is filled with cells that have received the status of granular leukocytes, but have mutated and never function in their natural role.
6. Megakaryoblastic. One of the rare variants of acute myeloid leukemia, which always develops and progresses simultaneously with bone marrow fibrosis, which should be taken into account when selecting treatment tactics.
7. Erythroleukemia (acute Di Guglielmo syndrome). The rarest type of cancer of the blood, characterized by malignancy of erythroblasts.

Causes of acute myeloid leukemia

The question of why becomes possible development in the hematopoietic organs, the process of malignancy, which affects white blood cells with a granular structure, has still not lost its relevance among specialists. The immediate causes of AML lie in chromosomal abnormalities of the cell, but why they arise remains a mystery to hemato-oncologists today. The only thing that experts can say with certainty is the existence of a certain group of risk factors that increase a person’s chances of developing acute myeloid leukemia in his circulatory system.

Among the main prerequisites that can cause a person to develop dangerous disease, special place occupy:

1. Increased level radiation exposure. For each person, the dangerous limit of exposure to radiation may be different, which is associated with the susceptibility of his body to ionizing rays.
2. Direct long-term contact (usually 1-5 years is enough for the development of the disease) with chemicals and toxins, both at work and at home. This factor provokes the development of aplasia (destruction) of part of the bone marrow, leading to the production of defective cells by the remaining hematopoietic tissue.
3. Consumption of certain amounts in excess of the permissible dose medicines. Cytostatics pose a particular danger. Also, the risk is posed by the banal Aspirin, familiar to everyone from childhood, and some antibiotics used uncontrollably.
4. Long-term exposure to the human body from influenza or herpes viruses. These pathological microorganisms are capable of triggering the onset of mutation in the blast cells of the bone marrow.

Worth knowing! Acute myeloid leukemia is very often diagnosed if the patient has a history of diseases such as Down and Bloom syndromes, as well as Fanconi anemia. But even in the absence of these genetic pathologies hereditary factor the risk of developing symptoms of acute myeloid leukemia is very high. If cancer pathologies were noted among blood relatives of previous generations circulatory system, the chances that their descendants will suffer from it increase several times.

How does acute myeloid leukemia manifest and what symptoms accompany it?

All negative manifestations that can suggest that a person’s hematopoietic structures of the bone marrow are affected and acute myeloid leukemia has begun to develop are provoked by a lack of healthy, fully mature leukocytes, platelets and red blood cells. Symptoms of oncopathology of this type, caused by the disappearance of blood cells that were not affected by the mutation, and their replacement by abnormal blood cells that are not capable of natural functioning, are expressed in the following:

• fatigue that constantly haunts a person, not associated with any physical stress;
• , expressed in pallor skin;
• the appearance of traces of subcutaneous hemorrhages and bruises without mechanical impact;
• violation of body thermoregulation, increased sweating or chills-like syndrome not related to ambient temperature;
• frequent bleeding, both external and internal, prolonged healing of inflammatory damage to the mucous membrane and minor skin wounds.

These negative symptoms appear unexpectedly and actively progress. Often the first doctor to suspect acute myeloid leukemia is the therapist or dentist to whom the patient turns with such complaints. Often the first symptoms of the disease are completely non-specific and resemble a common cold, with the only difference being that they cannot be relieved for a long time, despite the use of the best medications.

On late stages The occurrence of acute myeloid leukemia in the hematopoietic organs is indicated by an increase in lymph nodes located in different parts of the body; the spleen or liver may also enlarge and obstructive jaundice may appear.

Diagnostics: blood tests and instrumental diagnostics

It is quite difficult to identify this blood disease, because its symptoms are often so non-specific that they do not cause any anxiety in a person and he is in no hurry to visit a doctor, thereby provoking the progression of the disease and its transition to the final, non-curable stage. Typically, acute myeloid leukemia becomes an incidental finding during a routine examination or detection of another disease. If a specialist suspects the development of the disease, the patient is referred to a hemato-oncologist to confirm or refute the diagnosis.

A specific one is assigned, which includes:

1. , which makes it possible to identify changes in the quantitative composition of blood cells and detect the presence of damaged granular leukocytes.
2. Bone marrow histology. Biopsy material intended for further research is taken from pelvic bones using a special needle.

Additionally, to identify the nature of the malignant blood lesion, which makes it possible to clarify the diagnosis, instrumental diagnostics– Ultrasound, CT or MRI. With these diagnostic techniques it is possible to identify the prevalence of the tumor process and the presence of secondary malignant lesions localized in the internal organs.

Treatment methods for myeloid leukemia - drug therapy (drugs of choice), surgery and traditional recipes

Therapy for acute myeloid leukemia consists of several areas. For achievement best result, is carried out using various procedures, selected based on the nature of the cancer lesion and the general condition of the patient.

The general treatment regimen for a dangerous disease includes the following measures:

1. . The gold standard, which is used to treat not only acute myeloid leukemia, but also other malignant blood lesions. For drug treatment aimed at destroying malignant blood cells, and (iv administration) are used, and subsequent maintenance therapy is carried out with Rubomycin or Bthioguanine. All courses and drug administration regimens are selected individually, based on the medical indications of each individual patient.
2. . Bone marrow tissue transplantation from a healthy donor is considered clinical practice hemato-oncologists are the most effective method therapy, in most cases leading the sick person to complete recovery.
3. Irradiation. This method of treatment has been practiced in the treatment of blood cancers for a long time, but has not yet gained popularity, which is due to its negative impact on the human body. In clinical practice, there is a high mortality rate in patients with oncology of the hematopoietic organs after courses of radiation therapy.

Prognosis for recovery from malignant blood lesions

In acute myeloid leukemia, oncohematologists usually give a conditionally unfavorable prognosis, since this blood disease is highly insidious and difficult to identify.

Based on statistical data, the prognosis for acute myeloid leukemia is as follows:

1. Among children in whom the disease is detected in a timely manner and adequately treated, complete recovery occurs in 60% of clinical cases.
2. Among adult patients, the onset of long-term remission is observed only in 35% of cases.
3. In elderly people over 60 years of age with a history of acute myeloid leukemia, treatment is usually unsuccessful, so only 10% of patients have a chance of prolonging life beyond 2-3 years.

Worth knowing! In the absence of therapeutic measures, the prognosis is disappointing - a person dies a few weeks after detection of acute myeloid leukemia. Most long term life in this case is 5-6 months. for this disease it is not practiced, because it has no effectiveness. All that can be achieved with the help of treatment with herbal decoctions is to reduce the manifestation of painful symptoms, but using such therapy independently, without the consent of the attending physician, is categorically unacceptable.

Prevention of myeloid leukemia

Unfortunately, it is not possible to prevent the development of this disease, since specific preventive measures There are no methods to avoid the development of a pathological condition. But anyone diagnosed with acute myeloid leukemia can improve their chances of living.

All that is required for this is compliance with certain rules after the therapy:

• mandatory scheduled visit to the doctor for preventive diagnostics;
• inadmissibility of changing place of residence with changing climatic conditions;
• ban on any physical procedures.

If these rules are followed, a person has a chance to avoid relapse of the disease and, accordingly, achieve conditional recovery, when the remission stage can continue until old age.

Informative video

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

Acute myeloid leukemia (C92.0), Chronic myeloid leukemia (C92.1)

Oncohematology

general information

Short description

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

Definition:
Acute myeloblastic leukemia (myeloid)- heterogeneous tumor disease blood system, characterized by clonal expansion of myeloblasts in the bone marrow, peripheral blood and other tissues and organs.

Protocol name: Acute myeloblastic leukemia in adults

Protocol code:

ICD-10 code(s):
C92.0 - acute myeloblastic leukemia
C92.1 - chronic myeloid leukemia (blast crisis phase)

Date of development of the protocol: 2015

Abbreviations used in the protocol:
* - drugs purchased as part of a one-time import
6-MP - 6-mecaptopurine
AH - arterial hypertension
BP - blood pressure
alloBMT - allogeneic bone marrow transplantation
ALT - alanine aminotransferase
Anti-Xa - antithrombotic activity
AST - aspartate aminotransferase
HIV - human immunodeficiency virus
g - gram
GGTP - gammaglutamyl transpeptidase
HSC - hematopoietic stem cells
Gr - gray
ED - unit of action
ELISA - enzyme immunoassay
CT - computed tomography
l - liter
LDH - lactate dehydrogenase
IU - international unit
mg - milligram
INR - international normalized ratio
MPO - myeloperoxidase
ml - milliliter
NE - naphthyl esterase
UAC - general analysis blood
OAM - general urine analysis
AML - acute myeloblastic leukemia
PCT - polychemotherapy
PCR - polymerase chain reaction
PET/CT - positron emission tomography/computed tomography
FFP - fresh frozen plasma
BMT - bone marrow stem cell transplantation
USDG - Doppler ultrasound
Ultrasound - ultrasound examination
FGDS - fibrogastroduodenoscopy
CP - cyclophosphamide
RR - respiratory rate
HR - heart rate
ECG - electrocardiography
EchoCG - echocardiography
NMRI - nuclear magnetic resonance imaging
6-MP - 6-Mercaptopurine
Ara-C - cytarabine
ATRA - all-trans retinoic acid
DNR - daunorubicin
Ida - idarubicin
CALGB - Cancer and Leukemia Group B
EBMT - European Group for blood and Marrow Transplantation
ECOG - Eastern Cooperative Oncology Group
FAB classification - French-American-British classification system
FISH - fluorescent in situ hybridization
HLA - human leukocyte antigen system
Mito - mitoxantrone
PICC- peripherally inserted central catheter

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

Level of Evidence Scale

Level of evidence Characteristics of the studies that formed the basis for the recommendations A A high-quality meta-analysis, systematic review of randomized clinical trials (RCTs), or a large RCT with a very low probability of bias (++), the results of which can be generalized to an appropriate population. IN High-quality (++) systematic review of cohort or case-control studies, or High-quality (++) cohort or case-control studies with very low risk of bias, or RCTs with low (+) risk of bias, the results of which can be generalized to an appropriate population . WITH Cohort or case-control study or controlled trial without randomization with low risk of bias (+). The results of which can be generalized to the relevant population or RCTs with very low or low risk of bias (++ or +), the results of which cannot be directly generalized to the relevant population. D Case series description or Uncontrolled study or Expert opinion

Classification

Clinical classification:

Classification of the World Health Organization [cit. by 2]
Acute myeloid leukemia with consistently detected translocations
AML with translocationt(8;21)(q22;q22); RUNX1-RUNX1T1;
AML with translocation inv(16)(p13.1q22) ort(16;16)(p13.1;q22); CBFB-MYH11;
AML with translocation t(9;11)(p22;q23); MLLT3-MLL and also
AML with translocation t(6;11)(q27;q23); MLLT4-MLL;
AML with translocation t(11;19)(q23;p13.3); MLL-MLLT1;
AML with translocation t(11;19)(q23;p13.1); MLL-ELL;
AML with translocation t(10;11)(p12;q23); MLLT10-MLL;
AML with translocation t(6;9)(p23;q34); DEK-NUP214 ;
AML with translocation inv(3)(q21q26.2) ort(3;3)(q21;q26.2); RPN1-EVI1;
AML (megakaryoblastic) with translocation t(1;22)(p13;q13); RBM15-MKL1;
Temporarily included:
AML with NPM1 mutation;
AML with CEBPA mutation.
Acute myeloid leukemia after previous chemotherapy;
(alkylating agents, topoisomerase II inhibitors, ionizing radiation);
Acute myeloid leukemia that does not meet the above criteria:
AML with minimal differentiation;
AML with signs of differentiation;
Acute myelomonocytic leukemia;
Acute monoblastic or monocytic leukemia;
Acute erythroid leukemia;
Acute megakaryoblastic leukemia;
Acute basophilic leukemia;
Acute panmyelosis with myelofibrosis;
Myeloid sarcoma;
Myeloid tumors associated with Down syndrome;
Acute leukemia of uncertain linearity;
Acute undifferentiated leukemia;
Acute leukemia with mixed phenotype and t(9;22)(q34;q11.2); BCR-ABL1;
Acute leukemia with mixed phenotype and t(v;11q23); MLL restructuring;
Acute leukemia with mixed phenotype, B/myeloid;
Acute leukemia with mixed phenotype, T/myeloid.

FAB (French-American-British)classification
Option M0: undifferentiated acute myeloid leukemia. Characteristic morphological features There are no blast cells.
Option M1: acute myeloblastic leukemia without signs of cell maturation. Some blast cells contain azurophilic granules, Auer rods, or both.
Option M2: acute myeloblastic leukemia with signs of maturation. Many blast cells contain azurophilic granules and Auer rods. M2Baso variant (acute myeloblastic leukemia with basophilia): blast cells with basophilic granules.
Option M3: acute promyelocytic leukemia. Hypergranular promyelocytes with multiple Auer rods. Option M3v: granulation is weakly expressed.
Option M4: acute myeloma-blastic leukemia. Blast cells bear characteristics characteristic of cells of the monocytic and granulocytic series. Option M4Eo:(acute myelomonoblastic leukemia with eosinophilia): increased content of eosinophilic cells in the bone marrow.
Option M5: acute monoblastic leukemia. Option M5a: blast cells without signs of maturation. Option M5b: blast cells with signs of maturation.
Option M6: acute erythromyelosis (acute erythroblastic leukemia, Di Guglielmo's disease). Erythroblasts make up more than 50% of all nucleated cells of the bone marrow, myeloblasts make up more than 30% of the cells of non-erythroid lineages.
Option M7: acute megakaryoblastic leukemia. Megakaryoblasts make up more than 30% of all nucleated cells in the bone marrow.

Phenotypic characteristics of FAB AML subtypes

AML subtype	Most common phenotype	Peculiarities
M 0	MPO+, HLA-DR+, CD13+, CD33+, CD34+, CD117+,CD7-/+, TdT-/+	Blasts - 90%, low value blast population SS and FS, possible expression of lymphoid markers: CD2, CD4, CD7, CD10
M 1	MPO+, HLA-DR+, CD13+, CD33+, CD34+ (weaker than in M0), CD117+,CD7-/+, TdT-/+, CD15-/+	Blasts - 90%
M 2	MPO+, HLA-DR+, CD13+, CD33+, CD117+, CD34+, TdT-/+, CD15+, CD65+/-, CD11b+/-	Blasts - 90%, possible weak expression of CD19
M 3	MPO+, HLA-DR-, CD13+, CD33+, CD34-/+, CD117-/+, CD15+, CD2-/+	Blasts are characterized by high values ​​of lateral light scattering (except for the CD2+HLA-DR- form)
M 4	CD34-/+, CD38+, CD4-/+, CD11b+/-,CD64+	CD2 expression correlates with M4E0 variant
M 5	MPO+, HLA-DR+, CD13+, CD33+, CD117-/+, CD15+, CD14-/+, CD36+, CD11b+/-, CD11c, CD4-/+	Large blasts, possible CD56 expression
M 6	CD71+, CD235+ (glycophorin A)	CD7 expression is not uncommon
M 7	MPO+, HLA-DR+, CD13+, CD33+, CD117-/+, CD34-/+, CD38+, CD61+, HLA-DR+/-, CD41+, CD42b+	Adhesion of platelets to blasts can distort research results

Cytochemical characterization of FAB AML subtypes

AML variant	Myelopyroxidase	Sudan black	Nonspecific Esterase
M 0	Negative	Negative	Negative
M 1	Positive in ≥3% cases	Positive	Negative
M 2	Positive	Positive	Negative
M 3	Positive	Positive	Negative
M 4	Positive	Positive	Positive
M 5	Negative	Negative	Positive
M 6	Negative	Negative	Negative
M 7	Negative	Negative	Negative

Diagnostics

List of basic and additional diagnostic measures:
Basic (mandatory) diagnostic examinations performed on an outpatient basis:

· myelogram.

Additional diagnostic examinations performed on an outpatient basis:




· general urine analysis;
· coagulogram;

biochemical blood test (total protein, albumin, total bilirubin, direct bilirubin, creatinine, urea, ALT, AST, glucose, LDH, C-reactive protein, alkaline phosphatase);

· ELISA for HIV markers;
· ELISA for markers of herpes group viruses;
· ECG;
Ultrasound of the abdominal organs (liver, spleen, pancreas, gallbladder, lymph nodes, kidneys), in women - pelvis;

The minimum list of examinations that must be carried out when referring for planned hospitalization:
· general blood test (calculation of leukemia, platelets in a smear);
· myelogram;
· blood type and Rh factor;
· biochemical blood test (total protein, albumin, total bilirubin, direct bilirubin, creatinine, urea, ALT, AST, glucose, LDH, C-reactive protein);
· Ultrasound of the abdominal organs, spleen, lymph nodes;
· Ultrasound of the pelvic organs - for women.

Basic (mandatory) diagnostic examinations carried out at the hospital level:
· general blood test (calculation of leukemia, platelets in a smear);
· myelogram;
· cytochemical study of blast cells (MPO, glycogen, alpha-NE, Sudan black);
· immunophenotyping “panel for acute leukemia” using flow cytometry;
· standard cytogenetic study;
· FISH research and molecular genetic research;
· HLA - typing;
· general urine analysis;
· blood type and Rh factor;
· coagulogram;
· determination of antithrombin III in plasma blood;
· quantitative determination of the level of D-dimers in blood plasma;
· biochemical blood test (protein, albumin, ALT, AST, bilirubin, alkaline phosphatase, GGTP, creatinine, urea, uric acid, electrolytes, LDH, glucose, C-reactive protein, immunoglobulin G, A, M);
· Rehberg test;
· ELISA for markers of viral hepatitis;
· ELISA for HIV markers;
· X-ray of the chest organs.

Additional diagnostic examinations carried out at the hospital level:
· pro-BNP (atrial natriuretic peptide) in blood serum;
· bacteriological examination of biological material;
· cytological examination of biological material;
· immunogram;
· histological examination biopsy (lymph node, iliac crest);
· examination of cerebrospinal fluid;
· PCR for viral infections (viral hepatitis, cytomegalovirus, herpes simplex virus, Epstein-Barr virus, Varicella/Zoster virus);
· echocardiography;
· Ultrasound of the abdominal organs (liver, spleen, pancreas, gall bladder, lymph nodes, kidneys), lymph nodes, and in women - the pelvis;
radiography paranasal sinuses nose;
· radiography of bones and joints;
· CT scan of the thoracic segment, abdominal segment, head, pelvis;
· MRI of the thoracic segment, abdominal segment, head, pelvis;
· FGDS;
· Doppler ultrasound of vessels;
· bronchoscopy;
· colonoscopy;
· 24-hour blood pressure monitoring;
daily allowance ECG monitoring;
· spirography.

Diagnostic measures carried out at the stage of emergency medical care:
· collection of complaints and medical history;
· physical examination (determining RR, heart rate, assessing the skin, determining the size of the liver, spleen, peripheral lymph nodes).

Diagnostic criteria:
The main criterion for AML is the presence of ≥20% blasts in the bone marrow, defined by immunological and cytochemical characteristics as myeloblasts. In the presence of t(8;21), inv(16), t(16;16) and in the case of acute erythroblastic leukemia, the diagnosis can be established with a smaller number of blasts.
Chronic myeloid leukemia in the blast crisis phase, the myeloid variant, is indistinguishable from AML by clinical and laboratory characteristics, but is diagnosed with a higher (≥30) number of blasts in the bone marrow or peripheral blood or the presence of extramedullary myeloid sarcomas.

Complaints about:
Clinical manifestations in AML are usually associated with changes in the CBC - cytopenia:
Neutropenia - bacterial infections, usually manifested by fever;
Anemia - weakness, fatigue. General weakness present in most patients and can be observed for several months before diagnosis;
Thrombocytopenia is a hemorrhagic syndrome in the form of petechiae, bleeding gums, recurrent nosebleeds, and hyperpolymenorrhea.
In some cases, ossalgia and B-symptoms (fever, weight loss, severe sweating) may be observed.

Anamnesis:
In some cases, patients may experience unmotivated weakness for several months before treatment.
Acute myelomonoblastic leukemia and acute myeloblastic leukemia are characterized by gingival hyperplasia and patients may initially consult a dentist.

Physical examination:
During physical examination, some patients (mainly with acute myelomonoblastic leukemia, acute monoblastic leukemia, blast crisis of chronic myeloid leukemia) reveal signs of proliferative syndrome - splenomegaly, enlarged lymph nodes, skin leukemides. Leukemids are detected in 13% of cases and have the appearance of nodes with a discolored skin over them.
Otherwise, manifestations are not very specific and include symptoms associated with anemia and thrombocytopenia.

Laboratory research:
UAC: As a rule, normochromic, normocytic anemia of varying severity is detected. The reticulocyte count is within normal limits or reduced. Approximately 75% of patients have thrombocytopenia. The average level of leukocytes at the stage of diagnosis is about 15x10 9 /l. 20% of patients have leukocytosis more than 100x10 9 /l. In 25-40% of patients, the leukocyte level does not exceed 5x10 9 /l. In 95% of cases when cytological examination Circulating blasts are detected in peripheral blood.
OAM: with severe hemorrhagic syndrome, hematuria may be observed
Bone marrow examination. Bone marrow is the main material for verifying the diagnosis. The myeloid orientation of blasts is confirmed based on the following signs:
. Auer rods according to light microscopy;
. according to a cytochemical study, a positive reaction to Sudan black B, myeloperoxidase, chloroacetate esterase or nonspecific esterase;
. Flow cytometry data identify the expression of myeloid antigens on blast cells. In 20% of AML cases there is coexpression of lymphoid markers (eg, CD7, CD19, CD2). “True” leukemia with a mixed phenotype (biphenotypic, bilinear) is rare (in 2-5% of cases) and is diagnosed based on scores on the European Group for the Immunological Characterization of Leukemia (EGIL) scale.

Revised scaleEGIL for biphenotypic acute leukemias.

Points	B-linear	T-linear	Myeloid lineage
2	СD79a	CD3 (cyt/m)	Anti-MPO
	cytIgM	Anti-TCR α/β	Anti-Lysocyme
	cytCD22	Anti-TCR γ/δ
1	CD19	CD2	CD13
	CD10	CD5	CD33
	CD20	CD8	CDw65
		CD10	CD117
0,5	TdT	TdT	CD14
	CD24	CD7	CD15
		CD1a	CD64
To establish a diagnosis of biphenotypic leukemia, at least 2 points are required in two lines

. standard cytogenetic study and FISH study can identify markers of a favorable prognosis (t(8;21)/RUNX1/AML1; inv(16)/CBFB/MYH11) and prognostically unfavorable markers (monosomal karyotype, t(9;11)/MLL, complex chromosomal aberrations, etc.) and therefore should be carried out in all patients before starting chemotherapy. About 50% of patients have some cytogenetic abnormality.
. molecular genetic research reveals genetic abnormalities such as FLT3, NMP1, KIT, CEBPA, MLL, which have prognostic significance and allow monitoring of minimal residual disease.

Instrumental studies: They are carried out to exclude syndrome-related diseases and diagnose complications.
· Ultrasound of the abdominal organs- detection of an increase in the size of the liver and spleen;
· CT scan of the thoracic segment- identification of infiltrative changes in lung tissue;
· ECG- identification of disturbances in the conduction of impulses in the heart muscle;
· EchoCG- assessment of the functional state of the heart muscle;
· FGDS- assessment of the condition of the mucous membrane of the esophagus, stomach, duodenum, detection of the source of bleeding;
· bronchoscopy- assessment of the condition of the mucous membrane of the trachea, bronchi, detection of the source of bleeding.

Indications for consultation with specialists:
· doctor for x-ray endovascular diagnostics and treatment - installation of a central venous catheter from a peripheral access (PICC);
· hepatologist - for the diagnosis and treatment of viral hepatitis;
· gynecologist - pregnancy, metrorrhagia, menorrhagia, consultation when prescribing combined oral contraceptives;
· dermatovenerologist - diagnosis of skin and venereal diseases;
· infectious disease specialist - suspicion of viral infections;
· cardiologist - for the correction of persistent hypertension, chronic heart failure, cardiac arrhythmias;
neurologist - to determine diagnosis and treatment acute disorder cerebral circulation;
neurosurgeon - determination of indications for neuro surgical interventions;
· nephrologist (efferentologist) - determination of indications for therapy renal failure;
· oncologist - diagnosis of solid tumors;
otorhinolaryngologist - for the diagnosis and treatment of inflammatory diseases of the paranasal sinuses and middle ear;
ophthalmologist - visual impairment, inflammatory diseases eyes and appendages;
· psychiatrist - treatment of mental disorders;
· psychologist - for diagnosis and correction of psychological disorders
(depression, anorexia, etc.); proctologist - anal fissure, paraproctitis;
· thoracic surgeon - to determine indications and perform pleural puncture and lung biopsy;
· resuscitator - treatment of severe sepsis, septic shock, acute pulmonary injury syndrome with differentiation syndrome and terminal conditions, installation of central venous catheters;
· rheumatologist - suspicion of diffuse connective tissue disease;
· transfusiologist - for the selection of transfusion media in case of a positive indirect antiglobulin test, ineffective transfusions, acute massive blood loss;
· urologist - infectious and inflammatory diseases of the urinary system;
· phthisiatrician - diagnosis of tuberculosis;
· surgeon - determination of indications for surgical interventions;
· maxillofacial surgeon - infectious and inflammatory diseases of the dentofacial system.

Differential diagnosis

Differential diagnosis.
The leading criterion for diagnosing AML is an increase in the number of blasts by more than 20% and data from cytochemical studies and flow cytometry, which make it possible to determine whether the blasts belong to the myeloid lineage.
There are not many diseases in which there is an increase in the number of myeloblasts in the bone marrow - myelodysplastic syndrome with excess blasts, chronic myeloid leukemia and other chronic myeloproliferative diseases.
The number of blasts in myelodysplastic syndrome does not exceed 20%. In chronic myeloid leukemia in the accelerated/blast crisis phase and other myeloproliferative diseases, cytogenetic/molecular genetic studies (t(9;22) and/or chimeric BCR/ABL gene are detected in 100% of cases), anamnestic data and the presence of splenomegaly.

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Treatment

Treatment goals:
Achieving and maintaining remission.

Treatment tactics:
Non-drug treatment:
Mode:
General protective.
Diet:
Neutropenic patients are not recommended to follow a specific diet. Currently, there is no evidence to support the effectiveness of the so-called “neutropenic diet” (level of evidence B). .

Drug treatment:
The main stages of chemotherapy for AML are induction of remission, consolidation of remission, and under certain conditions, hematopoietic stem cell transplantation is performed as post-remission therapy.

Induction of remission.
The standard regimen for inducing remission in patients aged 18-60 years is the 7+3 regimen: anthracyclines (daunorubicin at least 60 mg/ or idarubicin 10-12 mg/m2 or mitoxantrone 10-12 mg/m2 for 3 days ) and cytarabine for 7 days at a dose of 100-200 mg/m2 in the form of an extended intravenous infusion. This regimen allows achieving remissions in 60-80% of young adults and 40-60% of older adults. (Level of evidenceB)
In patients younger than 50 years, increasing the dose of daunorubicin resulted in an increase in remission rate (59% vs 74%) and median overall survival (19 months vs 34 months) without an increase in toxicity or mortality. In the group with unfavorable cytogenetic abnormalities, the differences in overall survival were not statistically significant. In patients over 50 years of age, no significant increase in remission rates or survival was observed. In patients aged 60-65 years, increasing the dose of daunorubicin to 90 mg/m2 was accompanied by an increase in the likelihood of achieving remission after the first course, but did not affect overall survival.
The AML-10 study compared the induction and consolidation efficacy of different anthracyclines and concluded that idarubicin and mitoxantrone had superior disease-free survival, but the study used daunorubicin at a dose of 50 mg/m 2 . In addition, the study found no differences in remission rates in any group.
Anthracyclines and anthracyclines play a role important role in the treatment of AML, their optimal doses still need to be clarified, but these drugs are quite toxic. In the Hematological protocol scientific center(Moscow) AML-01.10, a high total dose of anthracycline antibiotics was used (720 mg/m2), which was accompanied by long periods of myelosuppression and required an increase in intercourse intervals and modification of the protocol in 28% of patients. It is known that in the long term, increasing the total dose of doxorubicin from 450 to 600 mg/m2 leads to an increase in the incidence of heart failure from 3.3% to 8.7%.
No other changes to the regimen (increasing the dose of cytarabine, adding etoposide, fludarabine, etc.) led to an increase in its effectiveness.
Both American and European research groups use the 7+3 regimen to induce remission in elderly patients, with some trials escalating the dose of daunorubicin to 90 mg/m2 in patients under the age of 65 years. Alternative regimens, especially in poor somatic status, are low doses of cytosar and hypomethylating agents. When using Ara-C at a dose of 10 mg/m 2 2 times a day subcutaneously for 10 days once a month, remission is achieved in 18% of cases and the one-year survival rate is 25%. (Level of evidenceC)
In elderly patients (over 60 years of age) and patients with AML as a result of myelodysplastic syndrome, induction therapy can be carried out with hypomethylating drugs - decitabine or azacitidine *.
Decitabine at a dose of 20 mg/m 2 /day as a one-hour infusion for 5 consecutive days every 4 weeks has a comparable effect on overall survival as low doses of Cytosar. (Level of evidenceB)
Azacitidine. A randomized study of the use of azacitidine at a dose of 75 mg/m2/day in patients over 45 years of age, with a relatively small percentage of blasts (20-30%), showed an increase in median survival from 16 to 24 months and the rate of complete remission from 16 to 18 % (Level of Evidence B) .

Consolidation of remission.
Currently, two main post-remission therapy strategies are used - chemotherapy and a combination of chemotherapy with hematopoietic stem cell transplantation, with allogeneic transplantation having the advantage.
The large CALGB study demonstrated the benefit of 4 courses of HiDAC (3 g/m2 every 12 hours on days 1, 3, 5) compared with intermediate (400 mg/m2 days 1-5 as an extended infusion) and standard (100 mg/m2 m 2 IV on days 1-5) in patients with CBF gene abnormalities and, to a lesser extent, in patients with a normal karyotype. 5-year disease-free survival in the group of patients with CBF abnormalities (inv(16); t(8;21) with high-dose consolidation was 78% compared to 16% with standard treatment. With a normal karyotype, the differences are 40% and 20%, respectively. The same group demonstrated the superiority of 3 courses of HiDAC compared to one course in patients with CBF (Corebinding factor) abnormalities. In this group of patients, no other interventions such as prolonging intensive consolidation from 3 to 8 courses, adding other chemotherapeutic agents, or performing autologous or allogeneic HSC transplantation are superior to high-dose cytosar monotherapy. However, the CBF group is heterogeneous and in the presence of other genetic abnormalities, such as c-kit or EVI1 mutations, there is a risk of relapse.
In patients without CBF abnormalities in the presence of a compatible donor optimal method post-remission therapy is allogeneic HSC transplantation, which is usually performed after the first course of consolidation. In the absence of a donor, patients undergo chemotherapy aimed at consolidating remission. Currently, there is no consensus on which regimen and how many courses are optimal for consolidation in patients under 45 years of age.
The AML 8B study proved that in patients aged 46-60 years, high-dose consolidation did not lead to an increase in 4-year survival, which was 32% in the intensive group and 34% in the standard group (p = 0.29). In the intensive group, the relapse rate was lower compared to the standard group (75% vs 55%), but treatment-related mortality was higher (22% vs 3%). This is why the reduction in relapse rates did not lead to an increase in overall survival in the intensive consolidation group.
In young patients, especially with a normal karyotype and without unfavorable molecular genetic markers, high-dose consolidation, especially with the use of high doses of Cytosar, is used by most cooperative groups, but its results remain unsatisfactory and a high risk of relapse remains.
Results from protocols that do not use high doses of cytarabine are fairly comparable to studies that do. According to a Japanese study, after four courses of standard consolidation without maintenance therapy, the 5-year overall survival rate was 52.4%. In a German study using high-dose consolidation, the 5-year overall survival rate was 44.3%. The results of the studies are influenced not so much by the doses and drugs used in consolidation, or the number of courses, but by the transplantation activity.
A study from the Finnish group showed that 5-year overall and disease-free survival were comparable after two or six courses of intensive consolidation.
Thus, in patients from the high and intermediate risk group, in the absence of the possibility of allogeneic transplantation of HSCs, consolidation is performed in at least two courses. In most cases, with the exception of young patients with a normal karyotype and without additional molecular markers of poor prognosis, standard-dose regimens can be used.
Autologous HSC transplantation can be used as an element of consolidation in patients from the intermediate cytogenetic risk group in the absence of a compatible donor or as a “bridge to allogeneic transplantation.” In case of low chemosensitivity of the tumor (lack of remission after completion of induction) and the presence of unfavorable cytogenetic abnormalities, the results of autologous GCS transplantation do not differ from standard chemotherapy.
Interesting data were obtained in the AML96 study. Survival in patients from the intermediate-risk group (post-remission treatment score groups) after autologous transplantation was 62% and significantly exceeded not only the chemotherapy group (41%), but also the group of patients with allogeneic HSC transplantation (44%).
In elderly patients, according to the Cancer and Leukemia Group B randomized trial, increasing the dose of Cytosar does not improve response and increases the incidence of side effects, especially neurotoxic ones. There is currently no consensus on post-remission therapy in elderly patients. The issue is decided mainly individually depending on the general condition and comorbid status, and the choice can vary from allogeneic transplantation of HSCs with reduced-intensity conditioning to palliative therapy or adequate care without specific treatment.

Maintenance therapy.
In contrast to acute lymphoblastic and acute promyelocytic leukemia, the role of maintenance therapy in AML remains controversial. Many centers do not use supportive care in young adults. Maintenance therapy may increase disease-free survival but has no effect on overall survival. Moreover, the effectiveness of maintenance therapy is more important in the absence or minimal intensity of consolidation. In the case of high-dose consolidation, maintenance therapy does not lead to a statistically significant increase in relapse-free survival.

Therapeutic tactics during induction treatment.

The choice of remission induction course for all patients is determined according to age:
· 18-45 years old;
· 46-55 years old;
· >55 years old.
All patients of the first age group (18-45 years old) undergo a course of remission induction according to the scheme: 7+3 (DNR 60 mg/m2). If after the first induction, remission is established on days 14 or 21, then the patient is transferred to the consolidation stage-I. If there is no remission, then the patient is treated according to the “double induction” program.
Patients of the second age group (46-55 years) are recommended to take 2 courses according to the scheme: 7+3 (DNR 45 mg/m2). If after the first induction, remission is established on days 14 or 21, then the patient is transferred to the consolidation stage-I. If there is no remission, then the patient is also treated according to the “double induction” program.
For patients >55 years of age, 2 courses of remission induction with low doses of Cytarabine (AraC) are recommended over 14-28 days. Exception: For patients aged 55-60 years, with a satisfactory somatic status and the absence of severe concomitant pathology, a course of PCT according to the scheme: 7+3 (DNR 45 mg/m 2) is possible.
Before starting PCT, all patients require immunophenotyping, a standard cytogenetic study of the bone marrow, and a molecular cytogenetic study using the FISH method.
Calculation of doses of cytostatic drugs - cytosine arabinoside Cytarabine, daunorubicin - is carried out in accordance with the surface area of ​​the patient's body. Doses of cytotoxic drugs are recalculated after each course of induction and consolidation, since many patients lose weight during treatment. Reducing drug doses during the course is unacceptable in any case, with the exception of the situations specified below.

Reduction of drug doses is carried out:
· in case of renal failure;
· with liver failure.



After completing the first course of chemotherapy, a program of accompanying therapy is necessary.
The first control bone marrow puncture is performed 14 or 21 days after the end of the first induction course (but not later than 21 days).
Remission is stated when the bone marrow punctate contains 5% or less blast cells (counting at least 200 cells), when the number of neutrophils in the peripheral blood is more than 1.5 x10 9 /l, when the number of platelets is more than or equal to 100x10 9 /l, when absence of extramedullary foci of leukemic growth.
Patients who achieve complete remission after 7+3 undergo a second course of 7+3 consolidation.
If in patients in the control bone marrow puncture, performed on days 14 or 21 after the 7+3 course, remission is not achieved (more than 5% of blast cells), then the second course of induction is recommended to begin immediately according to the “double induction” strategy, regardless of the parameters of peripheral blood and not expecting their complete recovery. Exception: the start of the course is postponed in case of intractable infectious complications (pneumonia, invasive aspergillosis, disseminated candidiasis, sepsis, etc.), the issue of prolonging the break after the first induction is decided individually. In other cases, the second induction course continues according to the 7+3 scheme (the maximum duration of the break between courses is 28-35 days).
If the “double induction” strategy is not used, then the puncture is repeated after 7 days and if the drug in the first puncture is paucicellular, then the cytological examination is repeated after another 7 days (on the 28th day of the break).
In some patients, the period of deep cytopenia (less than 1-1.5x10 9 /l of leukocytes) after the induction course can be long (more than 4 weeks). A control bone marrow puncture is still carried out no later than 21 days after the course, regardless of peripheral blood parameters.
If in this puncture, produced during the period of persisting cytopenia for 21 days, less than 5% of blast cells are determined, then the start of the next course can be delayed until days 28-35 and a repeat puncture must be performed. The maximum period for extending the course interval after 7+3 in the absence of blastosis is 35 days. A second control puncture is required to restore the indicators.
If the cytopenia after the first induction course is very deep - the number of leukocytes is 1.0x10 9 /l or less and persists by 35 days after the course - then it is recommended to perform a repeated puncture of the bone marrow with a myelogram count, assess the likelihood of infection with viruses (peripheral blood and bone marrow for markers hepatitis viruses, herpes group), perform a trephine biopsy (if possible, an immunohistochemical study of antigens of the herpes family viruses and hepatitis viruses in the trephine biopsy should also be performed).
If a trephine biopsy specimen against the background of deep cytopenia lasting more than 35 days reveals normocellular or hypercellular bone marrow, regardless of the percentage of blast cells in the punctate, then the patient can begin a second course of induction.
Before the start of the second course of induction, the doses of cytostatic drugs are recalculated, since there is a high probability that after the first course the patient’s weight has decreased and the overall body surface has changed.
This course requires the same implementation of accompanying therapy algorithms as the first induction course (antiemetic therapy, replacement therapy blood components, antibiotic therapy for the development of infectious complications).
If in a patient after the second course of induction on days 14 or 21, more than 5% of blast cells are detected in the bone marrow control punctate, then a resistant form of acute leukemia is determined, and the patient is transferred to treatment protocols for refractory AML:
18-45 years old:
· If there is a donor, conducting a FLAG course;
· In the absence of a donor, conducting a HAI course.
46-55 years:
· Conducting the course according to the scheme: 7+3 Ida.
>55 years:
· With ECOG<3 баллов, пациенту проводиться 5+2 Ida;
· If ECOG>3 points, the patient is treated with “small dose of cytosar” or 6-MP (the use of research treatment protocols is also possible).
When a diagnosis of AML is made for all patients and siblings Necessarily carry out HLA typing (medium resolution).

Therapeutic tactics during consolidation treatment.

Remission consolidation programs are determined based not only on the age of the patients (as in the induction course), but the patient’s risk group is also of no small importance:
18-45 years old:
High-risk group: 1-2 courses according to the 7+3 Mito scheme
Low-risk group: 3 courses according to the NA regimen (dose of Ara-C 2-3 g/m2).
46-55 years:
High-risk group: 1-2 courses according to the 7+3 scheme (DNR 45 mg/m2).
Low-risk group: 3 courses of NA (dose of Ara-C 2 g/m2).
>55 years:
With ECOG > 3 points and in the presence of severe concomitant pathology, 2 courses of “small doses” Cytarabine - Ara-C are administered for 14-28 days.
With ECOG< 3 баллов и при отсутствии тяжелых сопутствующих патологий, рекомендовано проведение 2х курсов консолидации ремиссии по схеме 5+2.
The usual start date for the first consolidation course is 21-28 days (3-4 weeks) of the break after the second induction course, the maximum is 35 days (5 weeks). The maximum period is determined only by the presence of severe infectious complications that are not relieved during the post-course period.
If in the bone marrow puncture in patients with prolonged cytopenic syndrome (the number of leukocytes is 1.0x10 9 /l or less for 35 days after the course or more), an increased content of blast cells is determined, and in the trephine biopsy specimen significant hypoplasia of the bone marrow is detected (fat more than 80% ) therapy with low doses of cytarabine is recommended. If the trephine biopsy specimen reveals significant aplasia in the absence of an increased percentage of blast cells in the punctate specimen, then it is recommended to continue for another week (+42 days after the course) postpone the start of the consolidation course.
It is advisable for all patients, regardless of age, to examine the functional state of the heart muscle (before courses of consolidation and TCM). If a significant decrease in myocardial contractility is detected (ejection fraction less than 40%) or an increase in the concentration of atrial sodium uretic peptide by more than 100 ng/ml, it is advisable to consult a cardiologist and select courses without anthracyclines.
Doses of cytostatic drugs in consolidation courses are prescribed according to the patient’s body surface area determined before each course.
High dose cytarabine infusion should be given over 3 hours. With an excessively short administration (up to 1 hour) and a very long one (around the clock), the development of pulmonary distress syndrome associated with cytarabine endotheliopathy is possible. Premedication before the administration of cytarabine in high doses is carried out with dexamethasone 4-8 mg IV or methylprednisolone in terms of dexamethasone. 12 hours before the start of the NA course, the patient is prescribed eye drops with corticosteroids and completes all 5 days of the course + the first day of the break. Accompanying therapy is carried out according to the same principles as during the induction treatment period.
A control bone marrow puncture after each course of consolidation is performed:
1. After “high doses of Cytarabine” - on day 28;
2. After other PCT programs - for 21 days.
If, after consolidation programs, peripheral blood parameters are not restored by day 35, then it is necessary to perform the same algorithm for examining a patient with cytopenia as described for the induction course.

Low risk criteria
1) The presence of isolated t(8;21)(q22;q22); RUNX1-RUNX1T1
2) Presence of inv(16)(p13.1q22) OR t(16;16)(p13.1;q22); CBFB-MYH11
3) NPM1 mutation without FLT3-ITD (normal karyotype)
4) CEBPA mutation (normal karyotype)
If only one of the existing genetic abnormalities is detected at the onset of the disease, the patient is classified as a low-risk group. Otherwise (the presence of two or more genetic abnormalities), the patient is classified as a high-risk group, incl. with a normal karyotype.
If the patient was classified as a low-risk group, but after the first course of induction carried out at full doses, remission was not achieved, then the patient is classified as a high-risk group.

Further management.
Patients from the standard risk group and patients from the high risk group undergo 2 courses of consolidation of remission and then maintenance therapy for 2 years. Breaks in therapy are permissible only in cases of infectious complications, incl. febrile neutropenia, in the absence of effect from initial antibiotic therapy. Leukopenia (agranulocytosis) and/or thrombocytopenia by themselves are not sufficient grounds for interrupting chemotherapy during the induction period. If the number of leukocytes is less than 1.0x10 9 /l, but there are no infectious complications, therapy does not stop.
When invasive aspergillosis is established, glucocorticosteroid therapy is stopped immediately.
Chemotherapy is resumed in the absence of fever for 3 days (with persistent agranulocytosis - 5 days) from the moment it was interrupted (with the exception of invasive aspergillosis and septic shock).

Therapeutic tactics during maintenance treatment.

Initiation of maintenance therapy is possible if the following conditions are met:
Ø maintaining remission of the disease;
Ø absence of infectious complications;
Ø leukocytes more than 2.5x10 9 /l;
Ø granulocytes more than 750/μl;
Ø platelets more than 100x109/l.
Maintenance treatment is provided to patients from the “high-risk” group in remission after completing 2 courses of consolidation therapy who do not have an HLA identical donor.
All patients from 18 to 55 years old who have undergone 3-4 courses of induction/consolidation are given maintenance therapy according to a “rotating” program - 5+5 with 6-MP, 5+Cyclophosphamide.
Patients over 55 years of age receive maintenance therapy with 6-Mercaptopurine at a rate of 50 mg/m2 in a continuous mode with dose adjustment depending on changes in peripheral blood parameters:


Courses of maintenance therapy begin after the last course of consolidation against the background of fully restored peripheral blood counts and are carried out at intervals of 35 days.
The dose of all cytostatic drugs during maintenance therapy is reduced by 1/3 if, after the first course of maintaining remission, myelotoxic agranulocytosis develops (leukocytes less than 1x10 9 /l, granulocytes less than 0.5x10 9 /l) and thrombocytopenia (20x10 9 /l) .
Each subsequent course, carried out 35 days after the first day of the previous course, should begin when the platelet count is more than 100x10 9 / l and the leukocyte count is more than 2x10 9 / l. If the indicators are not restored, the course is carried out in doses of cytostatic drugs already reduced by 50%.
Maintenance therapy is carried out up to 2 years from the date of remission.
Bone marrow punctures are performed 1 time every 3 months, or if necessary, in particular, if a relapse of the disease is suspected.

Induction, consolidation and maintenance programs

Induction
7+3	Cytarabine Daunorubicin	100 mg/m2 2 times a day every 12 hours IV 30-minute infusion OR 100-200 mg/m2 continuous round-the-clock infusion on days 1-7 of the course
« Double induction»	Cytarabine Daunorubicin	Two courses 7+3 , carried out on the principle of double induction (the second course begins on the 22nd or 29th day from the start of the first, that is, on the 14th or 21st day of the break). 100 mg/m2 per day as a continuous infusion, days 1-7 45 or 60 mg/m2 IV infusion for 10 minutes per 50 ml of saline solution on days 1-3 of the course, 2 hours after the administration of cytarabine.
« Low doses of cytosar»	Cytarabine	10 mg/m2 (no more than 20 mg) 2 times a day subcutaneously for 14-28 days
Consolidation
7+3 Mito	Cytarabine Mitoxantrone	100 mg/m2 2 times a day every 12 hours 30-minute IV infusion on days 1-7 of the course 10 mg/m2 IV infusion for 30 minutes per 50 ml saline. solution on days 1-3 of the course, 2 hours after administration of cytarabine
5+2	Cytarabine Daunorubicin	100 mg/m2 2 times a day every 12 hours subcutaneously or intravenously on days 1-5 of the course 45 mg/m2 per day IV infusion for 10 minutes per 50 ml saline solution on days 1-2 of the course
H.A.	Cytarabine	2000 or 3000 mg/m2 2 times a day every 12 hours 3-hour IV infusion on days 1, 3, 5 of the course
Maintenance therapy
5+CF	Cytarabine Cyclophosphamide	650 mg/m2 per day intravenous infusion over 1 hour per 400 ml saline solution on the 1st day of the course
5+6-MP	Cytarabine 6-mercaptopurine	100 mg/m2 2 times a day every 12 hours subcutaneously or intravenously on days 1-5 of the course 60 mg/m2 per day orally on days 1-5
6-mercaptopurine	6-mercaptopurine	50 mg/m2 per day, taken orally under the supervision of OAC, up to two years
Programs of intensive courses of PCT for patients with refractory forms of AML
FLAG(±Ida)	Fludarabine Cytarabine G-CSF Filgrastim Idarubicin	30 mg/m2 IV for 30 minutes, days 1-5 of the course 2000 mg/m2 IV over 3 hours on days 1-5 of the course, 3.5 hours after fludarabine 300 mcg subcutaneously once a day 12 hours before the first administration of cytostatics 10 mg/m2 IV for 10 minutes on days 1, 3, 5 of the course
HAM	Cytarabine Mitoxantrone	3000 mg/m2 2 times a day every 12 hours IV drip for 3 hours on days 1-3 of the course 10 mg/m2 IV short infusion (no more than 30 minutes) per 50 ml saline. solution on days 3-5 of the course.
HAI	Cytarabine Idarubicin	3000 mg/m2 2 times a day every 12 hours intravenously for 3 hours on days 1, 3, 5 of the course
7+3 Ida	Cytarabine Idarubicin	100 mg/m2 2 times a day every 12 hours subcutaneously or intravenously on days 1-7 of the course 12 mg/m2 IV for 10 minutes, days 1-3 of the course
5+2 Ida	Cytarabine Idarubicin	100 mg/m2 2 times a day every 12 hours subcutaneously or intravenously on days 1-5 of the course 12 mg/m2 IV for 10 minutes, days 1-2 of the course
Induction, consolidation using hypomethylating drugs in patients over 60 years of age
Decitabine	Decitabine	20 mg/m2/day intravenously for 1 hour on days 1-5 of the course. Courses are repeated every 4 weeks. The answer is assessed after at least 4 courses.
Azacitidine	Azacitidine	75 mg/m2/day subcutaneously on days 1-5 of the course. Courses are repeated every 4 weeks. The dose can be increased to 100 mg/m2 if there is no effect after 2 courses. The answer is assessed after 4 courses.

Transfusion support.
Indications for transfusion therapy are determined primarily by clinical manifestations individually for each patient, taking into account age, concomitant diseases, tolerability of chemotherapy and the development of complications in the previous stages of treatment.
Laboratory indicators for determining indications are of auxiliary value, mainly for assessing the need for prophylactic transfusions of platelet concentrate.
Indications for transfusions also depend on the time after a course of chemotherapy - the predicted decrease in indicators in the next few days is taken into account.
Red blood cell mass/suspension (level of evidence)D):
· Hemoglobin levels do not need to be increased as long as normal reserves and compensation mechanisms are sufficient to meet tissue oxygen needs;
· There is only one indication for transfusion of red blood cell-containing media for chronic anemia- symptomatic anemia (manifested by tachycardia, shortness of breath, angina, syncope, de novo depression or ST elevation);
· A hemoglobin level of less than 30 g/l is an absolute indication for red blood cell transfusion;
· In the absence of decompensated diseases of the cardiovascular system and lungs, hemoglobin levels may be indications for prophylactic red blood cell transfusion in chronic anemia:

Platelet concentrate (level of evidence)D):
· If the platelet level decreases to less than 10 x10 9 /l or hemorrhagic rashes on the skin (petechiae, bruises) appear, a prophylactic transfusion of apheresis platelets is performed;
· Prophylactic transfusion of apheresis platelets in patients with fever, patients who are planning invasive intervention can be performed at a higher level - 20 x10 9 /l;
· In the presence of hemorrhagic syndrome of the petechial-spot type (nasal, gingival bleeding, menorrhagia, metrorrhagia, bleeding of other localizations), transfusion of platelet concentrate is carried out for therapeutic purposes.

Fresh frozen plasma (level of evidence)D):
· FFP transfusions are performed in patients with bleeding or before invasive interventions;
· Patients with an INR of ³2.0 (for neurosurgical interventions ³1.5) are considered candidates for FFP transfusion when planning invasive procedures. For planned interventions, it is possible to prescribe phytomenadione at least 30 mg/day intravenously or orally at least 3 days before the intervention.

Drug treatment provided on an outpatient basis:

Decitabine, 50 mg, vial;

· Idarubcin*, 5 mg, bottle;


· cyclophosphamide, lyophilisate/powder for solution for injection 200 mg, 500 mg, 1000 mg;

Antibacterial agents:
Azithromycin, tablet/capsule, 500 mg;
· amoxicillin/clavulanic acid, film-coated tablet, 1000 mg;
· moxifloxacin, tablet, 400 mg;
Ofloxacin, tablet, 400 mg;
· ciprofloxacin tablet, 500 mg;
· metronidazole, tablet, 250 mg, dental gel 20g;
· erythromycin, tablet 250 mg.

· anidulafungin, lyophilized powder for solution for injection, 100 mg/vial;



· clotrimazole, solution for external use 1% 15ml;

Fluconazole, capsule/tablet 150 mg.

· acyclovir, tablet, 400 mg, gel in tube 100,000 units 50 g;


Famciclovir, tablets, 500 mg.

· sulfamethoxazole/trimethoprim, tablet 480 mg.

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

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

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

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

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

· atenolol, 25 mg tablet;



· drotaverine, tablet 40 mg;


Levofloxacin, tablet, 500 mg;

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

· omeprazole, capsule 20 mg;
· povidone-iodine, solution for external use 1 l;
Prednisolone, tablet, 5 mg;
· dioctahedral smectite, powder for preparation of suspension for oral administration 3.0 g;

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

· chlorhexidine, solution 0.05% 100ml;

Drug treatment provided at the inpatient level:
− list of essential medicines indicating the release form (having a 100% probability of use):

Antineoplastic and immunosuppressive drugs:
· azacitidine*, 100 mg, vial;
Daunorubicin, lyophilized powder for the preparation of solution for injection or solution for intravenous administration 20mg;
· dexamethasone, solution for injection 4 mg/ml 1 ml;
Decitabine, 50 mg, vial;
· doxorubicin, for infusion, 10 mg;
· Idarubcin*, 5 mg, bottle;
· mercaptopurine*, tablet 50 mg;
· mitoxantrone, 10 mg, bottle;
· cyclophosphamide, lyophilisate/powder for solution for injection 200 mg, 500 mg, 1000 mg;
· cytarabine, lyophilized powder for the preparation of solution for injection 100 mg, 1000 mg.

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

Antibacterial agents:
· azithromycin, tablet/capsule, 500 mg, lyophilized powder for the preparation of solution for intravenous infusion, 500 mg;
· amikacin, powder for injection, 500 mg/2 ml or powder for solution for injection, 0.5 g;
· amoxicillin/clavulanic acid, film-coated tablet, 1000 mg, powder for solution for intravenous and intramuscular administration 1000 mg+500 mg;
· vancomycin, powder/lyophilisate for solution for infusion 1000 mg;
· gentamicin, solution for injection 80 mg/2 ml 2 ml;
· imipinem, cilastatin powder for solution for infusion, 500 mg/500 mg;
· sodium colistimethate*, lyophilisate for the preparation of solution for infusion, 1 million units/bottle;
· metronidazole tablet, 250 mg, solution for infusion 0.5% 100 ml, dental gel 20 g;
Levofloxacin, solution for infusion 500 mg/100 ml, tablet 500 mg;
linezolid, solution for infusion 2 mg/ml;
· meropenem, lyophilisate/powder for solution for injection 1.0 g;
· moxifloxacin, tablet 400 mg, solution for infusion 400 mg/250 ml
· ofloxacin, tablet 400 mg, solution for infusion 200 mg/100 ml;
· piperacillin, tazobactam powder for solution for injection 4.5 g;
tigecycline*, lyophilized powder for solution for injection 50 mg/bottle;
Ticarcillin/clavulanic acid, lyophilized powder for the preparation of solution for infusion 3000 mg/200 mg;
cefepime, powder for solution for injection 500 mg, 1000 mg;
· cefoperazone, sulbactam powder for solution for injection 2 g;
· ciprofloxacin, solution for infusion 200 mg/100 ml, 100 ml, 500 mg tablet;
· erythromycin, tablet 250 mg;
Ertapenem lyophilisate, for the preparation of solution for intravenous and intramuscular injections 1 year

Antifungal drugs:
· amphotericin B*, lyophilized powder for solution for injection, 50 mg/vial;
· anidulofungin, lyophilized powder for solution for injection, 100 mg/vial;
voriconazole, powder for solution for infusion 200 mg/bottle;
voriconazole, tablet, 50 mg;
· itraconazole, oral solution 10 mg/ml 150.0;
· caspofungin, lyophilisate for the preparation of solution for infusion 50 mg;
· clotrimazole, cream for external use 1% 30g, solution for external use 1% 15ml;
· micafungin, lyophilized powder for the preparation of solution for injection 50 mg, 100 mg;
· fluconazole, capsule/tablet 150 mg, solution for infusion 200 mg/100 ml, 100 ml.

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

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

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

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

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

Medicines that affect the blood coagulation system:
· aminocaproic acid, solution 5% -100 ml;
· anti-inhibitor coagulant complex, lyophilized powder for preparation injection solution, 500 IU;
· heparin, solution for injection 5000 IU/ml, 5 ml, gel in tube 100000 IU 50g;
· hemostatic sponge, size 7*5*1, 8*3;
· nadroparin, solution for injection in pre-filled syringes, 2850 IU anti-Xa/0.3 ml, 5700 IU anti-Xa/0.6 ml;
· enoxaparin, solution for injection in syringes 4000 anti-Xa IU/0.4 ml, 8000 anti-Xa IU/0.8 ml.

Other medicines:
· bupivacaine, solution for injection 5 mg/ml, 4 ml;
· lidocaine, solution for injection, 2%, 2 ml;
· procaine, solution for injection 0.5%, 10 ml;
· human immunoglobulin normal solution for intravenous administration 50 mg/ml - 50 ml;
· omeprazole, capsule 20 mg, lyophilized powder for the preparation of solution for injection 40 mg;
· famotidine, lyophilized powder for the preparation of solution for injection 20 mg;
Ambroxol, solution for injection, 15 mg/2 ml, solution for oral administration and inhalation, 15 mg/2 ml, 100 ml;
· amlodipine, tablet/capsule 5 mg;
· acetylcysteine, powder for solution for oral administration, 3 g;
· dexamethasone, eye drops 0.1% 8 ml;
Diphenhydramine, solution for injection 1% 1 ml;
· drotaverine, solution for injection 2%, 2 ml;
· captopril, tablet 50 mg;
· ketoprofen, solution for injection 100 mg/2ml;
lactulose, syrup 667 g/l, 500 ml;
· chloramphenicol, sulfadimethoxin, methyluracil, trimecaine ointment for external use 40g;
Lisinopril, 5 mg tablet;
· methyluracil, ointment for topical use in a tube 10% 25g;
· naphazoline, nasal drops 0.1% 10ml;
· nicergoline, lyophilisate for the preparation of injection solution 4 mg;
· povidone - iodine, solution for external use 1 l;
· salbutamol, solution for nebulizer 5 mg/ml-20 ml;
· smectitedioctahedral, powder for the preparation of suspension for oral administration 3.0 g;
· spironolactone, capsule 100 mg;
· tobramycin, eye drops 0.3% 5ml;
· torasemide, tablet 10 mg;
· tramadol, solution for injection 100 mg/2ml; capsules 50 mg, 100 mg;
· fentanyl, therapeutic transdermal system 75 mcg/h (for the treatment of chronic pain in cancer patients);
· folic acid, tablet, 5 mg;
· furosemide, solution for injection 1% 2 ml;
· chloramphenicol, sulfadimethoxine, methyluracil, trimecaine ointment for external use 40g;
· chlorhexidine, solution 0.05% 100ml
· chloropyramine, solution for injection 20 mg/ml 1 ml.

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

Other types of services provided at the stationary level:
Radiation therapy.
If, due to complications or technical difficulties, it is not possible to carry out a full program for the prevention of neuroleukemia with intrathecal injections of cytostatic drugs, then patients are recommended to undergo cranial irradiation at a dose of 24 Gy.

Indications for hematopoietic stem cell transplantation.
Transplantation of hematopoietic stem cells from a related donor is indicated for all patients in the first complete remission of acute lymphoblastic leukemia after completion of the induction/consolidation program who have HLA-identical siblings, with the exception of the low-risk group.

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

Surgical intervention:
Surgical intervention provided on an outpatient basis: not applicable.

Surgical intervention performed in inpatient conditions: If infectious complications develop, patients may also undergo interventions aimed at draining/eliminating the infectious focus.

Further management: UAC control - every 7-14 days, biochemical analysis blood (ALT, AST, bilirubin, creatinine, urea, electrolytes), control of cyclosporine concentration.
After completion of treatment according to the protocol, patients receive maintenance therapy for 2 years. Provided that remission of the disease is maintained, after the end of maintenance therapy, patients are registered as “D” and are observed by a hematologist at their place of residence for 5 years.

Indicators of treatment effectiveness:

Remission criteria:

Peripheral blood
· there are no blasts with Auer rods;
· there are no extramedullary lesions;
· absolute number of neutrophils more than 1x109/l;
· platelets more than 100x109/l.

Bone marrow
· less than 5% blasts in the bone marrow. The count must be made for at least 200 cells. If the result is ambiguous, then the study should be repeated at intervals of 5-7 days. In case of a “dry” puncture (dry tap), a histological examination of the bone marrow should be performed.

There is no dependence on transfusions of red blood cell containing media.
Absence of extramedullary lesions.

Neuroleukemia - in detection of blasts in the cerebrospinal fluid during cytological examination. Cytosis of more than 5 cells/µl may be observed, but this sign is optional.

Resistance - absence of remission on day 21 after the second induction course.

Relapse:
· Bone marrow relapse - detection during the next study of more than 5% blasts in the bone marrow in a patient with previously confirmed bone marrow remission;
· Neurorelapse - detection of blasts in the cerebrospinal fluid, regardless of cytosis or volumetric intracranial formation with histological confirmation. If a biopsy of the formation is not possible, PET/CT can be performed.
· Other extramedullary relapses - lesions of the skin, orbit, mediastinum, lymph nodes, tonsils, etc. are verified histologically and immunohistochemically.

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Acute megakaryocytic leukemia (acute megakaryoblastic leukemia, AML, AML M7) - a variant of acute myeloid leukemia, in which blast cells, which form the basis of the disease, are mainly represented megakaryoblasts(these are the precursor cells of megakaryocytes, from which, in turn, platelets are formed).

Incidence and risk factors

AML is a rare variant of acute myeloid leukemia. Its exact proportion among all cases of acute myeloid leukemia, according to various estimates, is 3-10% in children (most often younger) and 1-2% in adults. However, among young children with Down syndrome, it is, on the contrary, the most common type of acute myeloid leukemia.

The age distribution of AML has two peaks: one among young children (up to 3 years), the other among older adults.

Occasionally, AML develops from a preexisting myelodysplastic syndrome.

Signs and symptoms

Like other types of acute leukemia, AML is usually characterized by symptoms of anemia (fatigue, weakness, pallor, shortness of breath) and thrombocytopenia, that is, a lack of platelets (increased bleeding, bruising and bleeding). Resistance to infections is reduced.

Common in AML myelofibrosis(myelosclerosis) – the process of bone marrow replacement connective tissue. It also leads to anemia and thrombocytopenia and plays a role in the appearance of other symptoms: enlarged spleen (more often in children) and liver, bone pain, etc. In addition, myelofibrosis makes it difficult to take a bone marrow sample for diagnosis - so, a bone marrow puncture may be ineffective .

Diagnostics

The diagnosis of AML is usually made on the basis of morphological analysis of a bone marrow sample (detection of a sufficient number of megakaryoblasts - megakaryocyte precursor cells). The diagnosis is confirmed by immunophenotyping and cytochemical analysis. Cytogenetic analysis is used to determine chromosomal translocations; for example, in AML, the t(1;22) translocation is often encountered.

Treatment

In the treatment of AML, like most other types of acute myeloid leukemia, cytarabine and chemotherapy drugs of the anthracycline group (daunorubicin, idarubicin, mitoxantrone) are used. Other drugs are also used.

Due to the high probability of relapse in AML, many patients (except for patients with Down syndrome) after achieving the first remission are recommended allogeneic bone marrow transplantation, although it is not a guarantee against relapse.

Forecast

AML is one of the most malignant variants of acute myeloid leukemia. More than half of pediatric patients and 30-50% of adults can be put into remission, but then the majority of these patients experience a relapse. Even if bone marrow transplantation is performed after the first remission is achieved, five-year survival can be achieved in relatively few patients, usually young. The remaining patients are transferred to palliative care at some point. Specific data vary between publications, but still, survival figures for AML are significantly lower than the average results for acute myeloid leukemia.

However, patients with AML developing due to Down syndrome usually have a favorable prognosis. Most of them (up to 80%) can be cured.