Acute Myeloid Leukemias: Clinical Guidelines

List of Abbreviations

allo-HSCT – allogeneic hematopoietic stem cell transplantation

allo-BMT – allogeneic bone marrow transplantation

auto-HSCT – autologous hematopoietic stem cell transplantation

IV – intravenous

WHO – World Health Organization

IPT – immunophenotypic study

CT – computed tomography

MDS — myelodysplastic syndrome

MRD – minimal residual disease

MPD – myeloproliferative disease

AL – acute leukemia

AMLL – acute mixed-phenotype leukemia

AML – acute myeloid leukemia

s.c. – subcutaneous

CR – complete remission

PCR – polymerase chain reaction

HSCT – hematopoietic stem cell transplantation

BMT – bone marrow transplantation

US – ultrasound examination

CT – chemotherapy

ECOG – Eastern Cooperative Oncology Group

FAB classification – French-American-British classification

FISH – fluorescence in situ hybridization

MPO (myeloperoxidase) – myeloperoxidase

NCCN – National Comprehensive Cancer Network

** – vital and essential drugs

# – drug used off-label (not in accordance with the indications, contraindications, routes of administration, or dosages specified in the drug's package insert)

Terms and Definitions

Acute myeloid leukemias (AML) – clonal neoplastic diseases of the hematopoietic tissue associated with a mutation in a hematopoietic progenitor cell, resulting in a differentiation block and uncontrolled proliferation of immature myeloid cells [1, 2].

Complete remission (CR) in AML is defined as a state of the hematopoietic tissue in which bone marrow aspirate shows 5% or fewer blast cells with a normal ratio of all hematopoietic lineages, absence of blast cells with Auer rods, and absence of extramedullary sites, with a peripheral blood neutrophil count of ≥1.0*10⁹/L, a platelet count of ≥100*10⁹/L, and no extramedullary foci of leukemic growth. These parameters must remain stable for >1 month. It is established in the absence of data on minimal residual disease (MRD) status.

Complete remission with MRD negativity – CR with the absence in the bone marrow aspirate of the genetic marker detected at AML onset (by polymerase chain reaction (PCR)) or cells with an aberrant immunophenotype (by flow cytometry).

Minimal residual disease – a small population of tumor cells that cannot be detected by light microscopy but is identified by more sensitive research methods that detect 1 leukemic cell per 10^4–6 cells tested.

Complete remission with incomplete recovery – CR with persistent neutropenia (<1*10⁹/L) or thrombocytopenia (<100*10⁹/L).

Partial remission – all hematologic criteria for CR; reduction in the percentage of blast cells in the bone marrow aspirate to 5–25%; reduction in the number of blast cells in the bone marrow aspirate by at least 50% from baseline prior to treatment initiation. This criterion is used to evaluate the efficacy of AML treatment primarily in phase I–II clinical trials.

Overall survival. To evaluate overall survival, temporal parameters are analyzed for all patients who started treatment. The starting point is the day treatment began. Only death from any cause is considered an event (early mortality, death during remission from any cause, death during relapse). This analysis makes it possible to estimate the number of actually surviving AML patients undergoing the administered therapy.

Relapse-free survival. When evaluating relapse-free survival, data are considered only for patients who achieved CR. The starting point is the date CR was achieved. Events are considered to be relapse and death from any cause (during consolidation or maintenance therapy, from relapse, during remission from another cause, e.g., suicide). Only patients who were alive and in CR at the time of the analysis are censored.

Probability of maintaining CR (inverse of the probability of relapse). When evaluating the probability of maintaining CR, data are considered only for patients who achieved CR. The starting point is the date CR was achieved. Only disease relapse is considered an event. All patients who are alive in CR at the time of the analysis are censored. Patients who died during CR from treatment-related complications or other causes are censored on the date of death as patients who were in CR.

The probability of maintaining CR is the indicator that allows the true antitumor efficacy of a therapy to be evaluated without accounting for subjective factors such as nursing patients through treatment-related complications.

Event-free survival. This indicator evaluates the survival of all patients included in the analysis from the time treatment is initiated. Events include early mortality, failure to achieve CR within 2 months of treatment initiation, death during remission from chemotherapy (CT) complications or other causes, as well as disease relapse. Only patients who achieved CR within the first 2 cycles of CT and remain alive while maintaining CR at the time of analysis are censored.

Refractory form of AML, according to the majority of Russian experts, is diagnosed when CR is not achieved after completing 2 courses of induction therapy. It is important to note that, according to international criteria, resistance in AML can only be assessed 7 days after completing a polychemotherapy course. If a patient dies during a course of CT or within 7 days thereafter, it is impossible to determine whether the leukemia is refractory or not, and such patients are categorized as treatment failures with an indeterminate outcome.

Death in aplasia – death of a patient during induction therapy (1–2 cycles). This criterion combines the concept of "death in aplasia" – the death of a patient who survived for ≥7 days after the end of a CT course, during a period of myelotoxic agranulocytosis and hematopoietic tissue aplasia, in the absence of persistent leukemia proven by bone marrow puncture.

Death from an indeterminate cause – 1) death of a patient before completion of therapy; 2) death of a patient <7 days after completion of CT; c) death of a patient in whom blast cells are not detected in peripheral blood, but bone marrow puncture was not performed, ≥7 days after completion of induction therapy.

Currently, the concepts of 30-day and 60-day mortality are frequently used, i.e., death from any causes during the specified periods corresponding to the 1st and 2nd induction cycles; 60-day mortality was previously defined as "early mortality".

Hematological relapse — detection of more than 5% blast cells in bone marrow aspirate and/or an extramedullary tumor focus, including central nervous system leukemia (neuroleukemia).

Molecular/immunological relapse — detection of minimal residual disease (MRD) by flow cytometry and/or PCR, provided that an aberrant immunophenotype was analyzed or molecular testing was performed prior to therapy initiation.

Remission induction — the period of initial treatment aimed at the most rapid and significant reduction of tumor mass and achievement of complete remission (usually 1–2 courses). During this period, the administration of antineoplastic agents reduces the number of leukemic cells in the bone marrow by approximately 100-fold, i.e., at the time remission is confirmed, less than 5% of tumor cells are morphologically detectable in the bone marrow.

Remission consolidation. The second stage of acute leukemia (AL) therapy is the consolidation of the achieved antitumor effect (usually 1–2 courses). Currently, in most cases, consolidation is the most aggressive and high-dose stage in AL treatment. The objective of this period is to further reduce the number of leukemic cells remaining after induction, whenever possible.

Maintenance therapy — continuation of cytostatic treatment at lower doses than during the remission induction/consolidation period, or another (targeted) intervention directed against the potentially remaining tumor clone.

Prophylaxis or, if necessary, treatment of neuroleukemia. This stage spans all periods of program treatment: remission induction, consolidation, and maintenance therapy.

Bone marrow transplantation (BMT). This term encompasses hematopoietic stem cell transplantation (HSCT) from bone marrow, peripheral blood, and cord (placental) blood.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Acute myeloid leukemias (AML) are clonal neoplastic diseases of the hematopoietic tissue associated with a mutation in a hematopoietic progenitor cell, resulting in a differentiation block and uncontrolled proliferation of immature myeloid cells [1, 2].

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

AMLis a consequence of damage (mutation) in the genetic material of a clonogenic hematopoietic cell. This results in impaired cell cycle control, altered transcription processes, and abnormal production of several key proteins. Due to uncontrolled proliferation in the absence of differentiation, pathological cells accumulate. The fact that the pathogenesis of acute leukemia is associated with genetic aberrations is quite often confirmed by the detection of various chromosomal abnormalities (translocations, deletions, inversions, etc.). In most cases, the specific cause of AML remains unknown. However, several predisposing factors significantly increase the risk of developing this disease. A clearly proven link between ionizing radiation from an atomic bomb explosion, as well as chemotherapy and radiotherapy for other tumors, and an increased risk of acute leukemia has prompted the study of other potential leukemogenic factors (low-dose radiation, chemicals, smoking, electromagnetic waves). It has been proven that there is a dose-dependent relationship between smoking and the risk of acute leukemia, which is particularly evident in individuals over 60 years of age. A number of researchers suggest that about 20% of AML cases are a consequence of smoking. Long-term exposure of the human body to benzene produces a leukemogenic effect, but no correlation has been proven between low concentrations of this substance—which people most often encounter in the workplace—and an increased risk of developing AML. Studies on continuous exposure to low-dose radiation have not yet provided evidence supporting an increased incidence of acute leukemia. The relationship between prior chemotherapy or radiation therapy for other tumor diseases and an increased risk of AML was first noted in patients cured of Hodgkin lymphoma. It has been proven that the frequency of AML increases not so much due to the cumulative dose, but rather due to dose-rate intensity. The risk of secondary AML is highest between 2 and 9 years after the completion of prior chemotherapy. In 85% of cases, secondary leukemias occur within 10 years of the end of treatment [1, 2]. The etiology and specific factors leading to the development of secondary myeloid neoplasms have not been fully elucidated. Many genetic pathways and cooperative mutations are involved in the pathogenesis. Secondary AML associated with alkylating agents often presents with monosomy or partial deletion of chromosomes 5 and 7. This type of AML occurs relatively late, on average 5–7 years after treatment for the primary tumor.

1.3 Epidemiology of the Disease or Condition

It is estimated that AML affects an average of 3–5 people per 100,000 population per year. Furthermore, the incidence increases sharply after the age of 60, reaching 12–13 cases per 100,000 population in individuals over 80 years of age. The median age for this disease is 65 years. With a population of 140 million in Russia, the estimated incidence rate (according to European and American researchers) should be approximately 5,000 cases [3].

According to a registry study conducted by the Russian Acute Leukemia Study Group in several regions of Russia, the median age at AML diagnosis is 53 years, which is more than 10 years younger than in Western countries. These figures indicate both underdiagnosis of AML in older age groups and lower life expectancy in our country. According to the registry study, the incidence was 1.32 cases per 100,000 adult population. Despite the fact that AML is classified as a rare (orphan) disease, the social significance of treating this most formidable hematologic malignancy necessitates the organization of adequate specialized care that involves the interaction of multiple medical disciplines, a combination of clinical, laboratory, instrumental, and scientific studies, and continuity between inpatient and outpatient care [1, 2].

1.4 Features of Coding the Disease or Condition

C92.0 — Acute myeloid leukemia

Exclusion: accelerated phase / blast crisis of chronic myeloid leukemia (C92.1)

C92.3 — Myeloid sarcoma (chloroma, granulocytic sarcoma)

C92.5 — Acute myelomonocytic leukemia

C92.6 — Acute myeloid leukemia with 11q23 anomaly

C92.7 — Other myeloid leukemia

C92.8 — Acute myeloid leukemia with multilineage dysplasia

C92.9 — Myeloid leukemia, unspecified

C93.0 — Acute monocytic leukemia

C94.0 — Acute erythremia and erythroleukemia

C94.2 — Acute megakaryoblastic leukemia

C94.7 — Other specified leukemia

C95.0 — Acute leukemia of unspecified cell type

1.5 Classification of the disease or condition

List of acute myeloid leukemia variants (World Health Organization (WHO), 2016) [4].

The World Health Organization (WHO) classification (2017) categorizes all AML cases based on their cytogenetic and molecular genetic features, and it is precisely these features that define the clinicopathological groups:

• AML with recurrent genetic abnormalities

AML with t(8;21)(q22;q22); RUNX1::RUNX1T1

AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB::MYH11

Acute promyelocytic leukemia with t(15;17)(q22;q12); PML::RARA

AML with t(9;11)(p22;q23); MLLT3::KMT2A

AML with t(6;9)(p23;q34); DEK::NUP214

AML with inv(3)(q21q26.2) or t(3;3)(q21;q26.2); RPN1::EVI1

AML (megakaryoblastic) with t(1;22)(p13;q13); RBM15::MKL1

AML with BCR::ABL1

AML with mutated NPM1 gene

AML with biallelic mutation of the CEBPA gene

AML with mutated RUNX1 gene

• AML with myelodysplasia-related changes

• Therapy-related myeloid neoplasms

• AML, not otherwise specified (NOS)

Acute myeloid leukemia with minimal differentiation

Acute myeloid leukemia without maturation

Acute myeloid leukemia with maturation

Acute myelomonocytic leukemia

Acute monoblastic/monocytic leukemia

Pure erythroid leukemia

Acute megakaryoblastic leukemia

Acute basophilic leukemia

Acute panmyelosis with myelofibrosis (synonym: acute myelofibrosis, acute myelosclerosis)

• Myeloid sarcoma (synonyms: extramedullary myeloid tumor, granulocytic sarcoma, chloroma)

• Myeloid proliferations related to Down syndrome

Transient abnormal myelopoiesis (synonym: transient myeloproliferative disorder (TMD))

Myeloid leukemia associated with Down syndrome

The subgroup "AML with recurrent cytogenetic abnormalities" combines several AML variants:

• AML with t(8;21)(q22;q22); RUNX1::RUNX1T1;

• AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB::MYH11 (when these chromosomal rearrangements are detected, the diagnosis of AML is established regardless of the blast cell count in the bone marrow aspirate);

• Acute promyelocytic leukemia with t(15;17)(q22;q12); PML::RARA; RARA translocations with other partners are classified as distinct AML variants, e.g., AML with t(11;17)(q23;q12); ZBTB16::RARA; AML with t(11;17)(q13;q12); NUMA1::RARA; AML with t(5;17)(q35;q12); NPM1::RARA; AML with STAT5B::RARA.

The previously designated category "AML with 11q23 abnormalities KMT2A (MLL)" has been revised to "AML with t(9;11)(p22;q23); MLLT3::KMT2A". Other translocations distinct from those involving MLLT3 must be specifically noted in the diagnosis, e.g., AML with t(6;11)(q27;q23); MLLT4::KMT2A; AML with t(11;19)(q23;p13.3); KMT2A::MLLT1; AML with t(11;19)(q23;p13.1); KMT2A::ELL; AML with t(10;11)(p12;q23); MLLT10::KMT2A.

Three new subgroups were identified:

• AML with t(6;9)(p23;q34); DEK::NUP214;

• AML with inv(3)(q21q26.2) or t(3;3)(q21;q26.2); RPN1::EVI1;

• AML (megakaryoblastic) with t(1;22)(p13;q13); RBM15::MKL1, a rare variant of AL most frequently diagnosed in children.

Two new categories were identified in patients with AML with a normal karyotype:

• AML with a mutated NPM1 gene (nucleophosmin (nuclear phosphoprotein B23, numatrin));

• AML with a mutated CEBPA gene (CCAAT/enhancer binding protein (C/EBP) alpha). There is accumulating evidence that these mutations drive hematopoietic cell differentiation defects and belong to the so-called class II mutations.

Mutations in the fms-related tyrosine kinase 3 (FLT3) gene are detected in many AML variants and are classified as class I mutations, i.e., those that confer a proliferative and/or survival advantage to tumor cells. AML cases with FLT3 mutations are not segregated into a separate category; however, detecting these mutations is essential due to their prognostic significance. It is recommended not only to determine the presence of FLT3-ITD, but also to calculate the so-called allelic ratio. An allelic ratio is considered high at values ≥0.5 and low at values <0.5.

The previously distinguished subgroup "AML with multilineage dysplasia" in the WHO (2016) classification is defined as "AML with myelodysplasia-related changes". AML cases can be classified as "AML with myelodysplasia-related changes" if there are 20% blast cells in the bone marrow or peripheral blood and:

• there is a prior history of MDS or another MPN;

• there are cytogenetic abnormalities associated with myelodysplasia:

  • complex karyotype (3 or more chromosomal abnormalities);

  • unbalanced rearrangements: -7 or del(7q); -5 or del(5q); i(17q) or t(17p); -13 or del(13q); del(11q); del(12p) or t(12p); del(9q); idic(X)(q13);

  • balanced rearrangements (translocations): t(11;16)(q23;p13.3); t(3;21)(q26.2;q22.1); t(1;3)(p36.3;q21.1); t(2;11)(p21;q23); t(5;12)(q33;p12); t(5;7)(q33;q11.2); t(5;17)(q33;p13); t(5;10)(q33;q21); t(3;5)(q25;q34).

• multilineage dysplasia;

• "consistently detectable chromosomal abnormalities" are absent;

• no prior chemotherapy for another disease.

Acute myeloid leukemia, like other myeloid neoplasms arising as a result of prior chemotherapy for other diseases, is not classified as a separate AML entity.

In 2022, an article dedicated to the 5th revision of the WHO classification of acute myeloid leukemias was published; however, pending the release of the full printed version, it is currently advisable in practice to use the 2017 WHO classification [5].

Prognostic factors

Prognostic factors can be divided into groups [6]:

Group 1: factors based on patient characteristics and general health status;

Group 2: factors determined by the biological characteristics of the leukemic clone;

Group 3, noted in this chapter, is not an objective criterion, but a subjective yet exceptionally crucial factor, especially in the context of Russia: the adequacy of the administered chemotherapy.

Patient-related prognostic factors. Age is one of the universal, independent, and robust prognostic factors. Long-term treatment outcomes in AML patients older than 60 years are generally significantly worse compared to those in patients younger than 60 years. Outcomes in patients aged 60–65 years are virtually comparable to those in patients younger than 60 years if they receive treatment according to protocols adopted for younger individuals.

This is due to at least two reasons. First, the age-related increase in the frequency of adverse cytogenetic mutations: there is a gradual rise in cases with unbalanced chromosomal aberrations, complex, and monosomal karyotypes. Concurrently, the detection rate of balanced aberrations decreases, including favorable variants such as t(8;21), t(15;17) translocations, and chromosome 16 inversion inv(16). It is possible that this phenomenon may be driven by the age-related increase in the incidence of AML arising from antecedent MDS. Another feature determining the negative impact of age on AML prognosis is the development of comorbidities, the presence of which, all other things being equal, leads to a significant deterioration in general somatic status compared to younger patients.

Disease-related (AML) prognostic factors. Disease-related factors influencing treatment outcomes should be analyzed at all stages of treatment. This is because leukemia-associated prognostic factors allow for the assessment of tumor burden, blast cell sensitivity to antineoplastic drugs, the rate of leukemic cell eradication, and MRD levels.

First of all, it is necessary to consider readily available clinical and hematological parameters associated with an unfavorable AML course, such as leukocytosis >100*10⁹/L, and failure to achieve CR after the first induction cycle.

One of the most important prognostic factors associated with AML is the karyotype of the leukemic cells. Karyotype analysis is mandatory for all patients with suspected AML. Cytogenetic data allow for the verification of AML in cases where the exact blast cell count (less or greater than 20%) is less critical than the detection of characteristic chromosomal aberrations. This refers, in particular, to the so-called CBF (Core Binding Factor) AML, which encompasses cases with t(8;21) translocation and inv(16) inversion, regardless of the absence or presence of additional chromosomal aberrations. The 2022 WHO classification will expand this AML category, where not only the accurate diagnosis and risk stratification, but also the applied therapy will depend on the identified molecular genetic markers.

In addition, based on karyotype analysis, it is possible to stratify AML patients into 3 main groups: favorable, intermediate, and unfavorable prognosis (see Appendix G1). Categorizing AML patients into these groups is useful for selecting post-remission therapy tactics: choosing induction therapy, prescribing targeted therapy, using high-dose cytarabine**, and performing allogeneic HSCT (allo-HSCT). Recently, a number of Russian and American experts have recommended against standard chemotherapy altogether for patients with unfavorable karyotype anomalies due to its low efficacy, proposing instead alternative low-dose and targeted approaches, as well as combining intensive therapy with targeted drugs starting from the 1st induction cycle [7-9].

It should be noted that a normal bone marrow aspirate karyotype is observed in half of AML patients. In some cases, this may serve as a rationale for fluorescence in situ hybridization (FISH) or molecular genetic testing to search for specific chimeric genes or karyotype abnormalities associated with a particular clinical and hematological AML phenotype and prognosis: RUNX1::RUNX1T1 (t(8;21)), CBFB::MYH11 (inv16), PML::RARA (t(15;17)), KMT2A::MLLT3 (t(9;11)), DEK::NUP214, monosomies 5, 7, chromosome 3 inversion, and several others.

At the same time, it is also necessary to screen AML patients with a normal karyotype for mutations in specific genes with established prognostic potential. Molecular genetic risk stratification of AML patients is presented in Appendix G1.

Prognostic factors related to inadequate chemotherapy. In Russia, unfortunately, there is such an unfavorable prognostic factor as inadequate cytostatic treatment during the induction/consolidation period (reduction of calculated doses of cytostatic drugs and significant prolongation of intervals between cycles), or inadequate pretreatment. Already in the early 1970s, during the initial stages of AML chemotherapy development, American researchers proved that the efficacy of the "5 + 2" regimen is statistically significantly worse than that of the "7 + 3" regimen. More than 20 years ago, Russian studies demonstrated that reducing the doses of anthracyclines and related compounds and cytarabine** in the classical "7 + 3" regimen leads to a substantial worsening of overall and relapse-free survival rates [1].

In situations where cytogenetic and/or molecular testing has not been performed, it is impossible to determine the patient's risk group. However, one can be guided by the "synthetic" (combining molecular genetic and clinical features of AML) recommendations of European experts, who divide patients into 2 main groups: favorable and unfavorable prognosis. These recommendations, along with additions from Russian experts, are presented in Appendix G2 [1, 2, 7, 8]. Nevertheless, it should be emphasized that modern AML treatment is impossible without molecular genetic studies performed at disease onset.

1.6 Clinical presentation of the disease or condition

Mainly, clinical manifestations are associated with the replacement of normal hematopoietic tissue by tumor cells (anemia, thrombocytopenia, granulocytopenia), infiltration of various organs by them, and the production of various cytokines [10]. The onset of AML can be acute, accompanied by a significant fever, severe weakness, intoxication, bleeding, and severe infections. However, the diagnosis is often established incidentally during a routine medical examination or upon hospitalization for another reason. In elderly patients, anemia frequently triggers or worsens angina pectoris and cardiac arrhythmias, leading to hospitalization in a cardiology department.

No symptoms may be observed upon physical examination. However, enlargement of peripheral lymph nodes, liver, and spleen (which is most characteristic of myelomonocytic and monocytic leukemia), gingival hyperplasia (in myelomonocytic and monocytic variants), skin infiltration (in myelomonocytic and monocytic variants), hemorrhagic syndrome of varying severity (from petechial rashes to severe bleeding), bone pain, arthralgia, and neurological symptoms (meningeal signs – headache, nuchal rigidity, Kernig's sign, paresis of the facial, oculomotor, and other nerves, lower extremity paresis, etc.) are quite frequently detected. Blood tests may show non-specific changes: three-lineage cytopenia or anemia, or isolated leukopenia, leukocytosis, or thrombocytopenia. Blast cells may be undetectable in the peripheral blood smear or, conversely, account for 90–95% of all leukocytes. The leukocyte count also varies from less than 1.0 to 200–300*10⁹/L. In approximately 15% of cases, leukocytosis >100*10⁹/L is detected at disease onset.

Differential diagnosis of AML is straightforward because, with morphological confirmation (blast cells in the aspirate and/or peripheral blood), the diagnosis is obvious. Difficulties arise at the initial stages – during the analysis of peripheral blood smears when blast cells are absent. An elevated leukocyte count with a left shift in various infectious processes, as well as thrombocytopenia, anemia, and hemorrhagic syndrome in severe infections and sepsis, may cast doubt on the diagnosis of acute leukemia, but typical blast cells are never found in such cases. Differential diagnosis with infectious mononucleosis and certain other viral infections is often required, especially since the clinical symptoms (fever, sore throat, enlarged lymph nodes, liver, and spleen) may resemble those of acute leukemia. AML should also be differentiated from the blast crisis of chronic myeloid leukemia (the presence of the Philadelphia chromosome is not always helpful, as this marker can also be detected in newly diagnosed acute leukemias).

Extramedullary manifestations of acute leukemia deserve special attention, particularly neuroleukemia, which may be detected even at the time of acute leukemia diagnosis. The occurrence of neuroleukemia is caused by the metastasis of leukemic cells into the arachnoid and pia mater of the brain and spinal cord. In some cases, leukemic infiltration of peripheral nerves with various motor and sensory impairments is observed, or focal lesions of the brain parenchyma are detected. Neuroleukemia is characterized by meningeal and hypertensive syndromes: persistent headache is noted, vomiting and lethargy are possible, papilledema is detected, nystagmus, strabismus, and other signs of cranial nerve involvement may be present, and nuchal rigidity and Kernig's sign are revealed. In AML, neuroleukemia is quite rare at disease onset; however, AML with a monocytic line of differentiation (myelomonocytic, monocytic/monoblastic variants) does occur, particularly in those leukemia forms where inv(16) is detected (30% of such patients develop neuroleukemia in the absence of prophylaxis). In AML, extramedullary lesions include skin involvement (leukemids – most commonly purplish-bluish skin thickenings and nodules), the retina, gums, testes, and ovaries. Involvement of the lymph nodes, lungs, intestines, myocardium, and ureters has been described. In AML, extramedullary soft tissue lesions were previously referred to as "chloroma". Currently, the term "myeloid or granulocytic sarcoma" is used to denote soft tissue and organ involvement [1].

2. Diagnostics, medical indications and contraindications for diagnostic methods

Many recommended diagnostic methods for the disease and related conditions have limited evidence bases according to the scales for assessing the level of reliability of evidence and the level of conviction of recommendations due to the lack of clinical studies dedicated to them. Despite this, they are necessary elements of patient evaluation to establish a diagnosis and choose treatment tactics, as more effective and proven methods have not yet been developed.

Diagnostic criteria: The diagnosis of AML is established based on the detection of at least 20% blast cells in the bone marrow aspirate or peripheral blood, or, regardless of the percentage of blast cells, in the presence of chromosomal abnormalities pathognomonic for AML: t(8;21)(q22;q22) RUNX1::RUNX1T1, t(15;17)(q24;q21) PML::RARA, inv(16), or t(16;16)(p12;q23) CBFB::MYH11.

2.1 Complaints and Anamnesis

Clinical manifestations in AML are typically associated with hemogram abnormalities, namely cytopenia:

• Neutropenia – bacterial infections, usually manifesting as fever.

• Anemia – weakness, fatigue. General weakness is present in the majority of patients and may be observed for several months prior to diagnosis.

• Thrombocytopenia – hemorrhagic syndrome in the form of petechiae, gingival bleeding, recurrent epistaxis, menorrhagia, and metrorrhagia.

• In some cases, ossalgia and B symptoms (fever, weight loss, profuse sweating) may be observed.

• In some cases, patients may experience unmotivated weakness for several months before seeking medical attention.

Acute myelomonocytic leukemia and acute monocytic leukemia are characterized by gingival hyperplasia, and patients may initially consult a dentist.

2.2 Physical Examination

Comment: upon physical examination, some patients (mainly with acute myelomonocytic leukemia, acute monocytic leukemia, and blast crisis of chronic myeloid leukemia) show signs of "proliferative" syndrome – splenomegaly, enlarged lymph nodes, and skin leukemids. Leukemids are detected in 13% of cases and appear as nodules with altered skin color overlying them [16]. Myeloid sarcoma presents with extramedullary tumor formations of various localizations [17]. Otherwise, manifestations are non-specific and include symptoms associated with anemia and thrombocytopenia.

2.3 Laboratory Diagnostics

Comment: as a rule, at AML onset, normochromic, normocytic anemia of varying severity is detected. Reticulocyte counts are within normal limits or decreased. Approximately 75% of patients have thrombocytopenia. The average leukocyte level at the time of diagnosis is about 15*10⁹/L; 20% of patients have leukocytosis >100*10⁹/L.

Leukocyte differential must not be performed on an automated analyzer. It is recommended to examine at least 200 leukocytes in a peripheral blood smear.

Comments: additionally, if indicated, at any stage of AML diagnosis and treatment, other blood parameters may be investigated: blood levels/activity of alkaline phosphatase isoenzymes, blood pancreatic amylase activity, serum protein fraction ratio by electrophoresis, blood level of iron, serum transferrin, blood immunoglobulins, blood erythropoietin, blood paraproteins, blood calcitonin, blood troponins I, T, blood procalcitonin, serum folic acid, nephron function assessment via creatinine clearance (Rehberg's test), tubular reabsorption tests, and others.

Comments: if changes are detected in screening test results and clinical indications are present, other coagulation parameters are investigated.

Comments: if indicated, additional urine tests are performed, for example, to rule out infection and identify the causative agent—Nechiporenko urine test, Zimnitsky urine test, various microbiological (culture) urine tests, and microscopic urinalysis. Also, when indicated at any stage of diagnosis and treatment of acute myeloid leukemia (AML), tests for hemosiderin in urine, free cortisol concentration in urine, alpha-amylase activity in urine, and others are performed.

Comments: microbiological (culture) testing (dysbiosis) using automated inoculation, microbiological (culture) testing of oral cavity discharge, intestinal microbiocenosis using culture methods, blood for sterility, and urine for bacterial pathogens may be performed.

• in all patients:

  • ABO blood group determination;

  • Rh blood group (Rh factor) D antigen determination;

  • determination of the subgroup and other minor blood groups A-1, A-2, D, Cc, E, Kell, Duffy;

  • compatibility testing prior to transfusion of blood components;

  • phenotyping for C, c, E, e, C^w, K, k antigens and detection of anti-erythrocyte antibodies;

• if necessary:

  • determination of HLA antigens;

  • determination of membrane immunoglobulin levels;

  • determination of anti-leukocyte antibody levels;

  • determination of anti-platelet antibody levels;

  • determination of the content of antibodies against erythrocyte antigens in blood serum.

GCP CLoE 5Grading of Recommendations Assessment, Development and Evaluation (GRADE) – C (Level of Evidence – 5)

Comments: the prescription of necessary tests and samples, as well as the selection of a specific type of blood component for transfusion (type of erythrocyte-containing blood component, type of platelet concentrate, type of plasma preparation) is carried out by the attending physician or transfusionist in accordance with the clinical situation and based on Order of the Russian Ministry of Health No. 1170n dated October 28, 2020 "On Approval of the Rules for the Provision of Medical Care to the Population in the Profile 'Transfusiology'", Order of the Russian Ministry of Health No. 1134n dated October 20, 2020 "On the Procedure for Medical Examination of the Recipient, Conducting Individual Compatibility Tests, Including a Biological Test, During Transfusion of Donor Blood and (or) Its Components", recommendations "Clinical Use of Erythrocyte-Containing Blood Components" (2018), Resolution No. 797 dated June 22, 2019 "On Approval of the Rules for Procurement, Storage, Transportation, and Clinical Use of Donor Blood and Its Components and on Invalidation of Certain Acts of the Government of the Russian Federation", and other regulatory acts (see Appendix A3.9).

Comment: bone marrow puncture (aspiration) is a mandatory routine diagnostic procedure. Bone marrow smears are examined using May–Grünwald, Pappenheim, or Wright–Giemsa staining. Trephine biopsy is not mandatory, except in situations with a so-called "dry tap" or very sparse bone marrow aspirate. It is recommended to examine at least 500 nucleated cells in the bone marrow smear.

To establish a diagnosis of AML in a peripheral blood or bone marrow smear, the presence of 20% or more blast cells is required. In AML with t(15;17), t(8;21), inv(16) or t(16;16), the proportion of blast cells may be less than 20%. In accordance with the current WHO classification (2016), the percentage of blast cells is calculated regardless of the proportion of the erythroid lineage.

Myeloblasts, monoblasts, and megakaryoblasts are included in the total number of blast cells. In cases of AML with monocytic and myelomonocytic differentiation, promonocytes (but not atypical/mature monocytes) are also counted as equivalents of blast cells. Erythroblasts are not included in the total number of blast cells.

When assessing the severity of dysplasia, multilineage dysplasia is defined as the presence of dysplastic features in 50% or more of the cells in 2 or 3 hematopoietic lineages. At least 25 erythroid cells, 25 granulocytes, and 6 megakaryocytes must be evaluated.

To verify the diagnosis of true erythroid leukemia, erythroid cells must account for >80% of all bone marrow cells upon bone marrow aspirate differential count, with proerythroblasts comprising ≥30%, excluding myeloblasts. According to the WHO nomenclature, proerythroblasts are immature erythrokaryocytes, whereas in accordance with the terminology of erythropoiesis cells by I.A. Kassirsky and G.A. Alekseev, these are erythroblasts and pronormoblasts. In true erythroid leukemia, dysmegakaryopoiesis is common, while dysgranulopoiesis is rare. If the bone marrow aspirate is hemodiluted with peripheral blood and the erythroid cell count is less than 80%, its evaluation can be performed using the bone marrow trephine biopsy [33].

Performing cytochemical analysis of bone marrow cells is essential, even if a high blast cell count is detected in the peripheral blood. This is because cytochemical reactions in certain cases may yield different results in peripheral blood and bone marrow cells, which can lead to an erroneous diagnosis. The diagnosis is based on the results obtained from bone marrow cells. Reactions for myeloperoxidase (MPO) or Sudan black, non-specific esterase (alpha-naphthyl acetate esterase, inhibited or not by sodium fluoride), and PAS (Periodic Acid Schiff) are used. The detection of MPO in 3% or more of blast cells indicates a myeloid line of differentiation. At the same time, its absence does not exclude a myeloid commitment of the cells, because in early myeloblasts and monoblasts, as well as megakaryoblasts and erythroblasts, MPO is <3% or undetectable. Staining with Sudan black is analogous to MPO, but is less specific. It is performed only when the myeloperoxidase reaction cannot be carried out. Non-specific esterase shows high diffuse or granular cytoplasmic activity (depending on the reaction method) in monoblasts and promonocytes, which should be completely or significantly inhibited by sodium fluoride. The PAS reaction in myeloblasts appears diffuse, in monoblasts and promonocytes — diffuse-granular, and in erythroblasts — as granules or blocks. Based on morphocytochemical examination of blast cells, approximately 90% of AML cases can be diagnosed; in the absence of MPO and non-specific esterase activity, immunophenotyping (IPT) by flow cytometry is required.

Comment: IPT analysis is always performed on bone marrow cells, even if a high blast cell count is detected in peripheral blood. Determining the percentage of blast cells by flow cytometry during initial diagnosis does not replace morphological counting, as the results of these two tests may not coincide [34].

To confirm the myeloid lineage of tumor cells, the expression of myeloid antigens must be evaluated. MPO is a lineage-specific marker of the myeloid line, a lysosomal enzyme of granulocytes. Less specific myeloid-associated antigens include CD11b, CD11c, CD13, CD15, CD16, CD33, CD64, CD65, CD66b, lysozyme, etc. A diagnosis of AML can also be established if MPO is not detected, provided the tumor cells express other, less specific myeloid markers and the lymphoblastic variant of acute leukemia is excluded.

There is no clear correlation between the French-American-British (FAB) morphocytochemical classification and IPT features. Most myeloid markers can be either positive or negative in different FAB variants of AML, with the exception of specific antigens CD41a and CD61, which are characteristic only of the megakaryocytic/platelet lineage. Even glycophorin A (CD235a), an erythroid lineage marker, may be negative in erythroid leukemia if the tumor cells originate from earlier precursors. Therefore, the FAB variant of AML cannot be determined based on IPT data.

Blast cells are considered positive for the expression of a membrane antigen if it is detected on 20% or more of the blast cells (cut-off value). For cytoplasmic markers (such as cytoplasmic CD3, MPO, lysozyme, nuclear TdT, etc.), a lower cut-off of 10% is used.

If obtaining a bone marrow aspirate is not possible, immunohistochemical examination of a bone marrow trephine biopsy is performed.

IPT analysis is performed using multiparametric flow cytometry (typically at least 6-color). When analyzing a trephine biopsy, immunohistochemical examination is performed. IPT analysis is particularly essential for establishing the diagnosis of AML with minimal differentiation, acute megakaryoblastic leukemia, and acute leukemia of ambiguous lineage. Acute leukemias of ambiguous lineage are rare types of leukemias and include cases that lack lineage-specific features (acute undifferentiated leukemia) or cases whose blast cells express markers of more than one differentiation lineage. In the European Group for the Immunological Characterization of Leukemias (EGIL) classification, ALAL are subdivided into acute biphenotypic leukemia, when a single tumor population expresses antigens of multiple differentiation lineages, and acute bilineal leukemia, characterized by 2 or more blast cell populations of different lineages. In the WHO classification, these variants are grouped under ALAL.

Comment: standard cytogenetic testing is an essential component of diagnostic procedures in a patient with suspected acute leukemia. Chromosomal abnormalities are detected in approximately half of patients with AML. Several translocations and inversions (and their variants) are categorized by the WHO as "AML with recurrent genetic abnormalities". Moreover, the detection of certain genetic abnormalities in the presence of 20% or more blast cells in the bone marrow is sufficient to establish a diagnosis of "AML with myelodysplasia-related changes". To determine the karyotype, analysis of at least 20 metaphases is considered reliable. Karyotypic abnormalities can also be established based on the examination of peripheral blood cells. The identification of specific cytogenetic abnormalities at the time of AML diagnosis can determine the therapeutic strategy for an individual patient; for example, the detection of complex karyotype changes or a monosomal karyotype indicates the need for a cytostatic approach different from standard therapy and requires discussing the feasibility of very early allo-HSCT incorporation into the AML treatment program, including performing allo-HSCT during aplasia after the 1st induction course.

Comment: in AML, RUNX1::RUNX1T1, CBFB::MYH11, PML::RARA, KMT2A, and EVI1 or loss of chromosomes 5q and 7 are evaluated. FISH is often necessary to identify KMT2A fusions in 11q23 region translocations. FISH can also be performed on bone marrow morphological and histological specimens.

• For all patients with a confirmed diagnosis of AML, to determine the prognosis of the disease and guide treatment tactics, it is recommended in certain cases to perform molecular genetic testing of blood or BM to detect mutations in NPM1, CEBPa, FLT3, TP53, ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, and ZRSR2 genes [9].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

• For all patients at the time of AML relapse or upon determination of refractory disease, it is recommended to repeat molecular genetic testing for FLT3-ITD and FLT3-TKD mutations to determine the need for tyrosine kinase inhibitors [1, 7, 8].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

Comment: The listed tests are performed on bone marrow aspirate to stratify patients into risk groups and determine treatment tactics, as well as to identify a marker for monitoring the dynamics of the tumor clone during therapy. If bone marrow sampling is not possible, determination of gene mutations on the patient's peripheral blood material is permitted.

Molecular genetic testing for FLT3 gene mutations is mandatory, since modern approaches to AML treatment involve the use of protein kinase inhibitors in patients with the FLT3-positive variant of the disease. AML with mutations in the NPM1 or CEBPA genes are defined by the WHO as separate categories. The NPM1 mutation is a marker for MRD assessment. The expression of ERG, MN1, EVI1, BAALC genes, and mutations in WT1, KIT, RAS, TET2, DNMT3A, IDH1, and IDH2 genes can be studied within clinical trials and, in rare cases of refractoriness or relapse, to search for new therapeutic approaches. In modern molecular diagnostics of AML, next-generation sequencing (NGS) is also widely used; so-called diagnostic panels comprising several dozen genes involved in AML pathogenesis have been created, which allow for the precise classification of the studied AML into a specific risk category.

Comment: in AML, RUNX1::RUNX1T1, CBFB::MYH11, PML::RARA, KMT2A, and EVI1 or loss of chromosomes 5q and 7 are evaluated. FISH is often necessary to identify KMT2A fusions in 11q23 region translocations. FISH can also be performed on bone marrow morphological and histological specimens.

Comment: to confirm the completeness of the achieved therapeutic response and its persistence, in accordance with current international guidelines, MRD assessment by flow cytometry (aberrant immunophenotype) must be performed at milestone time points, whereas for CBF-AML, only molecular MRD testing by PCR (quantitative assessment of RUNX1::RUNX1T1, CBFB::MYH1 expression, NPM1 mutations) is required. MRD by flow cytometry must be evaluated in a specialized laboratory (using at least an 8-color cytometer) utilizing all necessary monoclonal antibodies to achieve high sensitivity and specificity by combining two approaches: 1. identification of the leukemia-associated immunophenotype during the disease diagnosis period; 2. the "empty spaces" method, which consists of searching for cells that differ from normal counterparts [35, 36].

Determining the MRD status during treatment can alter the patient's prognosis and timely determine the appropriateness of allogeneic hematopoietic stem cell transplantation (allo-HSCT) [37].

Comment: microscopic examination of cerebrospinal fluid must be performed in all patients with pleocytosis ≥5/µL. To improve analysis accuracy, it is recommended to use a cytocentrifuge for preparing cerebrospinal fluid cytological specimens.

In AML overall, central nervous system involvement occurs in less than 5% of patients; however, in certain AML variants, particularly with monocytic differentiation, the probability of leptomeningeal involvement is higher.

It is advisable to maintain the platelet count prior to lumbar puncture at 30´10⁹/L and above. If the platelet level cannot be raised to 30*10⁹/L and above, in the absence of clinical signs of central nervous system involvement, the puncture may be deferred until the platelet count in the hemogram rises above 30*10⁹/L.

If the patient has leukocytosis above 100*10⁹/L, the first lumbar puncture should be postponed until the leukocyte count drops below 30–40*10⁹/L.

Neuroleukemia is diagnosed when any number of blast cells is detected in the cerebrospinal fluid obtained during the initial diagnostic lumbar puncture at any pleocytosis level, or when pleocytosis is 15/3 or greater (i.e., more than 5 cells per 1 µL).

Comment: preservation of primary biological material is carried out in the form of DNA and/or RNA isolated from bone marrow cells or frozen cells. The material may subsequently be needed for molecular testing to determine risk groups, as well as within the framework of clinical trials.

Comments: pleurocentesis with cytological examination of pleural fluid, bronchoalveolar lavage with cytological examination of lavage fluid, and lumbar puncture with cytological examination of cerebrospinal fluid are most frequently performed; however, as clinically indicated, a biopsy of any accessible organ and tissue may be performed followed by cytological examination, including oral cavity tissue micropreparations, peritoneal fluid, skin micropreparations, lymph node tissue specimens, tumor biopsies, bone-like tumor formations, liver tissue, large intestine tissue, uterine cavity aspirate, vaginal tissue, uterine tissue, prostate tissue, testicular tissue, kidney tissue, urinary bladder tissue, as well as punctates and touch imprints of retroperitoneal tumor biopsies.

• When examining cerebrospinal fluid (CSF):

  • Microscopic examination of cerebrospinal fluid, cell count in a counting chamber (determination of pleocytosis)

  • Determination of blood in the cerebrospinal fluid

  • Cerebrospinal fluid glucose level testing

  • Cerebrospinal fluid protein level testing

  • Tests for abnormal protein in the cerebrospinal fluid

  • Determination of hydrogen ion concentration (pH) in cerebrospinal fluid

  • Chloride level testing in cerebrospinal fluid

  • Microbiological (culture) testing of cerebrospinal fluid for aerobic and facultatively anaerobic opportunistic microorganisms

  • Microbiological (culture) testing of cerebrospinal fluid for non-spore-forming anaerobic microorganisms

  • Molecular biological testing of cerebrospinal fluid for Herpes simplex virus types 1 and 2

  • Detection of Herpes simplex virus types 1 and 2 DNA in cerebrospinal fluid by PCR

  • If the cell count is ≥5/µl, perform a cytological examination of cerebrospinal fluid cells. It is recommended to use a cytological centrifuge for preparing CSF cytological specimens to improve analysis accuracy

• When examining pleural fluid

  • Microscopic examination of native and stained pleural fluid specimens

  • Protein level testing in pleural fluid

  • Microbiological (culture) testing of sputum for aerobic and facultatively anaerobic microorganisms

• When examining lavage or ascitic fluid

  • Cytological examination of lavage fluid

  • Microscopic examination of lavage fluid

  • Microbiological (culture) examination of lavage fluid for aerobic and facultatively anaerobic microorganisms

  • Microscopic examination of bronchoalveolar lavage fluid for fungi (yeasts and molds)

  • Molecular biological examination of sputum and bronchoalveolar lavage fluid for Cytomegalovirus

  • Detection of Cytomegalovirus DNA in sputum and bronchoalveolar lavage fluid by PCR

  • Quantitative detection of Pneumocystis jirovecii DNA in sputum, endotracheal aspirate, and bronchoalveolar lavage fluid by PCR

LoR CGoE 5Level of Recommendation – C (Grade of Evidence – 5)

Comments: the most commonly performed biopsies are of skin lesions, bone marrow (trephine biopsy), and lymph nodes. However, depending on indications, a biopsy of any organ and tissue may be performed, including the oral mucosa, nasal mucosa, lung tissue, mediastinal tumor, spleen, liver, esophagus, stomach, colon, breast, bone, female genital organs, prostate gland, male genital organs, urinary bladder, kidney, and retroperitoneal tissues.

2.4 Instrumental Diagnostics

Comments: routine electrocardiogram recording is used; when clinically indicated, recording of the electrical activity of the cardiac conduction system, Holter heart rhythm monitoring, electrocardiographic data monitoring, and fetal cardiotocography are also performed.

Comments: MRI examinations of bone tissue, contrast-enhanced brain, contrast-enhanced spinal cord, pelvis, and contrast-enhanced spine are most frequently performed; as well as CT examinations of the facial skull, spine, paranasal sinuses, larynx, upper respiratory tract and neck, CT angiography of a single anatomical region, female pelvis, male pelvis, brain, abdominal cavity, contrast-enhanced abdominal cavity with intravenous bolus injection, and retroperitoneal space

Comments: also, when clinically indicated at any stage of AML diagnosis and treatment, ultrasound of other anatomical areas is performed (most commonly – ultrasound of soft tissues, joints, lymph nodes, pleural cavity, mediastinum, Doppler ultrasound of upper extremity vessels (arteries and veins), lower extremity vessels (arteries and veins), colon, transabdominal uterus and appendages, transvaginal uterus and appendages, mammary glands, thyroid and parathyroid glands, parathyroid glands, kidneys and adrenal glands, urinary tract, retroperitoneal space)

Comment: For diagnostic purposes during pregnancy, it is advisable to use magnetic resonance imaging methods as well as ultrasound, including lung tissue. Standard X-ray examination methods are undesirable during pregnancy due to the potential negative impact of X-rays on the fetus [44].

2.5 Other Procedures

• All patients with AML, taking into account potential intensive transfusion/blood transfusion therapy before and during treatment, are recommended an initial consultation (examination) by an anesthesiologist-resuscitologist to assess vascular access and, if indicated, place a central venous catheter [1].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).

• All patients with AML at any stage of diagnosis, monitoring, or treatment, when suspected of developing an infectious complication, are recommended to undergo diagnostic tests to clarify the localization of the infection, the type of infectious agent, and for dynamic monitoring during treatment (see sections 7.8–7.10) [45–47].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).

Comments: Infections are among the leading complications in the treatment of AML, particularly during the induction and consolidation of remission phases, and in the period of neutropenia. Infectious complications become more frequent in cases of resistant tumor variants, high-dose chemotherapy, concurrent hypogammaglobulinemia, and during periods of forced physical inactivity and strict bed rest.

Infectious complications in patients with hematological disorders are characterized by a wide variety in both etiology and localization of the infectious process, requiring a comprehensive set of laboratory tests for diagnosis and specific approaches to therapy that differ from the management of infections in patients without oncohematological diseases. The primary factor determining the development of infectious complications is neutropenia (neutrophils <0.5×10⁹/L) or leukopenia (leukocytes ≤1.000×10⁹/L), as well as the rate of neutrophil decline and the duration of neutropenia. The risk of infections increases with damage to the mucous membranes of the gastrointestinal tract (especially grade III–IV mucositis) and the presence of a central venous catheter (CVC).

Various viral, bacterial, and fungal infectious complications, including opportunistic infections, can develop in AML. Their timely diagnosis and treatment are critical components of successful patient management. Diagnostic studies include necessary imaging examinations (CT and MRI of involved areas, including brain CT when indicated); endoscopic, puncture, and biopsy procedures (including bronchoalveolar lavage, pleural puncture, and lumbar puncture when indicated); laboratory tests (including acid-base balance and blood gas analysis, and blood procalcitonin levels when indicated); cultures and other microbiological (cultural), molecular biological, microscopic, and other bacteriological tests for aerobic and facultatively anaerobic microorganisms (including opportunistic aerobic and facultatively anaerobic microorganisms), Pneumocystis, Mycoplasma, Legionella, Mycobacterium tuberculosis, fungi (yeasts and molds), Clostridia, and others.

• In all AML patients at any stage of diagnosis, monitoring, or treatment, electroencephalography is recommended as indicated to rule out a brain lesion site with abnormal electrical activity [1].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).

• In all AML patients at any stage of diagnosis, monitoring, or treatment, radiography of the affected area is recommended as indicated to rule out a lesion or the development of complications [1].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).

Comments: radiography of the entire skull in one or more projections, paranasal sinuses (including paranasal sinuses with contrast), spine, pelvis, femur, pericardium, mediastinum, kidneys and urinary tract, plain abdominal and pelvic radiographs, and fluoroscopy of the lungs are most frequently used.

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

The main principle of AML treatment is maximum efficacy (via treatment specificity and adequacy) combined with minimum toxicity (via rational supportive care). Long-term treatment outcomes for adult AML over the past 20 years have not fundamentally changed, despite improvements in supportive care and the introduction of several new drugs. According to large cooperative study groups, the average 5-year overall survival for patients under 60 years of age ranges from 35% to 50%, varying between 10% and 90% depending on the molecular and genetic characteristics of the tumor clone. Treatment-related mortality in these patients is 3%–18%. In elderly patients, long-term outcomes have remained practically unchanged over the past three decades, with 5-year survival not exceeding 10%–12%. AML remains an area of clinical hematology where intensive research continues in search of new therapeutic options [1, 2, 7, 8].

In 2017 and 2022, the European Expert Recommendations on the Diagnosis and Treatment of AML were published [7, 9]. Recommendations from the National Comprehensive Cancer Network (NCCN) have been developed and continuously updated in the USA for over a decade [8]. In recent years, significant progress has been made in understanding the molecular, genetic, and epigenetic foundations of AML development, enabling the identification of new diagnostic and prognostic biomarkers. The WHO classification (2017, 2022) incorporates the genetic and molecular variants of AML [9]. European recommendations on the optimal integration of allogeneic hematopoietic stem cell transplantation (allo-HSCT) into frontline AML therapy have been published [48].

For all ALs, there are several main stages of therapy: remission induction, consolidation, maintenance therapy (see Appendix A3.1) and neuroleukemia prophylaxis for certain AL variants [1,2]. The initial treatment period, the goal of which is the most rapid and substantial reduction of the tumor burden and achievement of CR, is called the remission induction period (usually 1–2 courses). If CR is not achieved after 2 induction courses, primary resistance (refractory disease) is stated, and patients receive therapy according to treatment protocols for refractory forms of leukemia. It must be emphasized immediately that failure to achieve CR after the 1st induction course is a reliable factor for a poor long-term prognosis of AML; therefore, immediately after the 1st course (provided that the doses and duration of cytostatic exposure were adequate), patients should be considered as potential candidates for allo-HSCT [1, 2, 47].

The second stage of AL therapy is consolidation of remission (consolidation of the achieved antineoplastic effect). Currently, in most cases, consolidation is the most aggressive and high-dose stage in the treatment of AL. The objective of this period is, if possible, to further reduce the number of leukemic cells remaining after induction. Consolidation (usually 1–2 courses) is followed by a period of anti-relapse or maintenance treatment. For different variants of AL, the duration, intensity, and composition of maintenance therapy vary.

A fundamental step in the treatment of certain AML variants (promyelocytic with leukocytosis >10*10⁹/L, myelomonocytic and monoblastic, AML with extramedullary involvement, AML with initial leukocytosis of 30*10⁹/L or more) is prophylaxis or, if necessary, treatment neuroleukemia.

For many AML patients, a key stage of treatment is allo-HSCT. This term encompasses hematopoietic stem cell transplantation using bone marrow, peripheral blood, and cord (placental) blood. This stage is most effective when performed during the 1st (less commonly 2nd) complete remission (CR) of AML. The outcomes of allo-HSCT outside of CR are extremely poor. A group of Russian experts believes that allo-HSCT is indicated for all AML patients under 60 years of age in the 1st CR who have not undergone molecular genetic testing, naturally taking into account transplantation risks and comorbidities. If cytogenetic and molecular studies have been performed, indications for allo-HSCT in the 1st CR of AML are evaluated according to international criteria. The information presented in Appendix G4 can serve as a guide in deciding whether to perform HSCT in an AML patient in the 1st CR. If the risk of relapse with chemotherapy exceeds the integrated risks following allo-HSCT, the decision is made in favor of HSCT [47].

The principles of AML treatment and protocols are determined by the patient's age.

3.1. Treatment of patients with acute myeloid leukemia aged 18–60 years

Comment: delaying the start of therapy for a short period (5–7 days) from the onset of disease diagnosis does not affect treatment efficacy, early mortality rates, or long-term outcomes of AML therapy.

Comment: if upon admission the patient presented with one of the aforementioned conditions, but it is successfully resolved or controlled as a result of intensive supportive care, cytostatic CT may be initiated in 3–7 days. If supportive care for the concomitant condition is accompanied by AML progression in the form of leukocytosis, an increased percentage of blast cells in the peripheral blood, or if the baseline leukocyte count is 100*10⁹/L or higher, it is advisable to add #hydroxycarbamide** at a dose of 100 mg/kg/day to the complication management [50, 51] and/or leukapheresis and, if necessary, plasmapheresis for tumor lysis syndrome prophylaxis. If the patient's condition cannot be stabilized within a maximum of 7 days due to extremely severe disease-related complications or severe comorbid pathology, palliative cytostatic treatment (e.g., low-dose cytarabine**) may be considered.

Comment: The inclusion of gemtuzumab ozogamicin in chemotherapy regimens is most justified in CBF-AML and AML with mutated NPM1, i.e., favorable AML variants. The 7-day administration of cytarabine** can be performed at a dose of 100–200 mg/m² either twice daily (100 mg/m² each) as a short infusion, or as a continuous intravenous (IV) infusion (200 mg/m²) combined with a 3-day administration of anthracyclines and related compounds as a short infusion (daunorubicin** at a dose of at least 60 mg/m², or idarubicin** at a dose of 12 mg/m², or #mitoxantrone** at a dose of 10 mg/m²). The choice of a specific drug (daunorubicin**, idarubicin**, or mitoxantrone**) does not significantly affect final outcomes. Doxorubicin** is not used in the "7+3" course for AML remission induction. Gemtuzumab ozogamicin combined with "7+3" is administered intravenously once daily on days 1, 4, and 7 of the course at a dose of 3 mg/m² (maximum one 5 mg vial). An alternative administration schedule for gemtuzumab ozogamicin is possible: at a dose of 3 mg/m² (maximum one 5 mg vial) administered intravenously once on one of the first 4 days of the "7+3" course (day 1, day 2, day 3, or day 4 (Appendix A3.1) [54-57, 58-60].

Comment: considering the lack of data on increased remission rates despite significantly higher treatment toxicity. This is permissible only within clinical trials.

Comment: possible dosage options for #cytarabine** during remission consolidation courses are 1 g/m², 1.5 g/m², or 3 g/m² twice daily on days 1, 3, and 5 (dosages of 1.5 and 1 g/m² are off-label). Currently, there are some discrepancies in cytarabine** dosage recommendations between European and American investigators. European investigators have reached a consensus that the optimal dose of #cytarabine** in consolidation courses is 1–1.5 g/m² [7], whereas American investigators in the NCCN guidelines maintain a dose of 1.5–3 g/m² [8]. Gemtuzumab ozogamicin combined with high/intermediate doses of cytarabine** is administered at a dose of 3 mg/m² (maximum one 5 mg vial) once on the first day of the cycle[54-56]. If high-dose consolidation is not feasible, an alternative option may be to administer 2 additional "7+3" consolidation courses with idarubicin** or #mitoxantrone** at induction doses without gemtuzumab ozogamicin due to potential overlapping toxicity with anthracyclines and related compounds (see Appendix A3.1).

Comment: The main phase of prophylaxis consists of 5 lumbar punctures during remission induction/consolidation, followed by 3 more punctures every 3 months during maintenance therapy – for a total of 8 lumbar punctures with intrathecal administration of 3 drugs. Foreign researchers do not recommend neuroleukemia prophylaxis in patients without neurological symptoms, whereas Russian researchers consider neuroleukemia prophylaxis a mandatory stage of AML treatment in the aforementioned situations.

Comment: after completing 1–2 courses of low-dose cytarabine** and resolving all complications, it is advisable to return to high-dose consolidation comprising at least 2 courses. Low-dose cytarabine** may remain the primary therapy for 3 years only in patients with acute erythroid leukemia and megakaryoblastic leukemia.

Comment: venetoclax** therapy at a dose of 400–600 mg is administered in combination with azacitidine** 75 mg/m² for 7 days, decitabine 20 mg/m² for 5 days, or low-dose #cytarabine** 20 mg/m²/day for 10 days (see Appendix A3.1). Venetoclax** dose adjustment is required when coadministered with CYP3A inhibitor drugs (in accordance with the product labeling). To prevent massive tumor lysis, a step-up dosing schedule of venetoclax** is provided at the start of treatment, with therapy suspended until symptom resolution upon the appearance of clinically significant laboratory/clinical signs of tumor lysis syndrome.

#Sorafenib**: Strength of recommendation – B (level of evidence – 2), and midostaurin**: C (level of evidence – 5), respectively.

Comment: midostaurin dosing regimen: 50 mg twice daily orally on days 8–21 of the course concurrently with "7 + 3" induction therapy and 4 high-dose cytarabine** consolidation courses, followed by maintenance therapy with midostaurin** 50 mg twice daily for at least 1 year. Midostaurin** maintenance therapy is also provided after allo-HSCT. The duration of midostaurin maintenance therapy may be extended up to 2 years, regardless of whether allo-HSCT was performed or not.

Dosing regimen for #sorafenib** in young patients: 400 mg orally twice daily on days 10–19 of each induction course; thereafter, 400 mg twice daily starting on day 8 of each consolidation course, followed by maintenance therapy with #sorafenib** 400 mg twice daily for at least 1 year (regardless of whether allo-HSCT was performed).

Dosing regimen for #sorafenib** in elderly patients: 400 mg orally twice daily on days 1–7 of each induction course; thereafter, 400 mg orally twice daily on days 1–28 for two 28-day courses concurrently with 2 courses of consolidation with intermediate-dose cytarabine** (2 g/m²/day, days 1 and 5 of the 28-day course), followed by maintenance therapy with #sorafenib** 400 mg orally twice daily for one year.

Comment: maintenance cytostatic, hypomethylating, or targeted therapy (depending on the induction and remission consolidation program the patient received for AML) should be carried out for at least 1 year from the start of treatment (4 induction/consolidation courses and 6 maintenance courses) or for 2 years from the start of therapy (4 induction/consolidation courses and 9–12 maintenance courses) (see Appendix A3.1).

Comment: auto-HSCT is considered by some foreign researchers as a post-induction therapy option in intermediate-risk patients upon achieving MRD-negative AML remission [73]. However, the Russian expert group does not consider auto-HSCT as a post-remission treatment option for AML patients because auto-HSCT can only be a phase of therapy provided that absolutely adequately performed induction and consolidation treatment and mandatory MRD monitoring are implemented. It can only be recommended within clinical trials.

Comment: For high-risk patients, including those with FLT3-ITD, allo-HSCT should be considered an obligatory stage of treatment. For this specific group of patients, it is extremely important to perform HLA-typing of the patient prior to the start of the 1st induction course, and after achieving the 1st CR, to initiate a search for potential donors. However, this recommendation is limited by several factors: age, patient performance status, availability of a donor, and the organizational capability to perform the allo-HSCT procedure. If the risk of relapse outweighs the integrated risks after allo-HSCT on chemotherapy, the decision is made in favor of HSCT.

Integrated risks associated with transplant-related mortality are given in Appendix G4. To make a final decision on this issue, the patient must be referred for a consultation at a transplant center.

Comment: except for cases of AML with t(8;21) and inv(16) with persistent high-level MRD, for which allo-HSCT is the optimal option. Allo-HSCT is also recommended for patients with AML with a normal karyotype and favorable molecular profile, but with hyperleukocytosis ≥100×10⁹/L and/or the presence of leukemids, and when AML is diagnosed during pregnancy.

Comment: the choice of treatment tactics for secondary AML should be made taking into account the cytogenetic variant of leukemia, the type of prior therapy, the patient's age and performance status, and the presence of complications. If an HLA-matched donor is available, the patient should be directed toward allo-HSCT.

Comment: upon achieving CR, if an HLA-matched donor is available, the patient should be directed toward allo-HSCT as soon as possible from the moment remission is achieved.

3.2. Treatment of patients with acute myeloid leukemia in the older age group (>60 years)

There are 3 main treatment "technologies" for AML in patients over 60 years of age. The first approach is intensive chemotherapy similar to that used in young patients, which in most cases is a combination of cytarabine** with anthracyclines and related compounds aimed at achieving CR. Allo-HSCT is the optimal post-remission option within this concept. The second approach is low-intensity therapy, in particular the use of low-dose cytarabine**, the efficacy of which, at least in patients aged 70 years and older, can be increased by prolonged use for 28 days, and pyrimidine analogues (azacitidine**, decitabine), including in combination with venetoclax**. The third choice is symptomatic (supportive) care aimed at reducing clinical symptoms and improving quality of life [1, 2, 7, 8]. The feasibility of a particular treatment option for AML in a patient over 60 years of age should be assessed based on the patient's age, objective determination of the severity of their condition, cytogenetic and molecular genetic variants of the disease, and analysis of comorbidities.

Comment: the choice of a specific drug from the anthracycline and related compounds group (daunorubicin**, idarubicin**, or mitoxantrone**) does not significantly affect the final outcomes [81]. A standard dose of daunorubicin** is considered to be 60 mg/m² [82].

Comment: candidates for low-intensity therapy also include patients aged 60 years and older with poor performance status, comorbidities, or organ dysfunction.

Comment: for this group of patients, hypomethylating therapy combined with venetoclax** [69] or combination therapy with low-dose cytarabine** combined with azacitidine** and idarubicin** (see Appendix A3.1) is preferred as low-dose cytostatic treatment.

• For AML patients older than 60 years, azacitidine** combined with venetoclax**, and in some cases azacitidine** monotherapy, can be recommended as the therapy of choice (see Appendix A3.1) [67, 69, 87].

GCR BLEL 2Grade of Recommendation – B (Level of Evidence – 2)

• For AML patients older than 65 years, decitabine monotherapy can be recommended as the therapy of choice (see Appendix A3.1) [84].

GCR BLEL 2Grade of Recommendation – B (Level of Evidence – 2)

Comment: decitabine therapy at a dose of 20 mg/m² for 5 days i.v. with a 28-day interval.

• For AML patients older than 60 years, venetoclax** therapy combined with azacitidine**, decitabine, or low-dose cytarabine** can be recommended [8, 64, 67, 69, 71].

GIB CLOE 4Grade of Recommendation – C (Level of Evidence – 4)

Comment: azacitidine** therapy at 75 mg/m² for 7 days s.c., decitabine 20 mg/m³ for 5 days i.v., or low-dose #cytarabine** 20 mg/m⁴/day for 10 days s.c. with venetoclax** 400–600 mg until intolerance or disease progression (see Appendix A3.1).

3.3. Therapy for relapsed and refractory forms of acute myeloid leukemia

Unfortunately, the majority of patients (60–70%) who achieve CR of AML experience disease relapse within 3 years. Overall, the prognosis for patients who develop a relapse is unfavorable, and therapeutic approaches are extremely scarce. Long-term survival depends on the possibility of achieving a second remission and performing HSCT as consolidation. Patients with very early relapse (remission duration of less than half a year), adverse cytogenetic abnormalities, and older age have a poor prognosis [1, 7]. Due to the unfavorable prognosis of relapsed patients, it is necessary to evaluate how feasible therapy is for a specific patient. An assessment of the prospect of long-term survival can be made based on the relapse prognostic index [88] (Appendix G5). The prognostic index can be used when determining the treatment strategy in a specific patient: 1) administering "curative" therapy using HSCT; 2) enrollment in a clinical trial evaluating new drugs; 3) palliative care.

NCCN guidelines, which are also followed by Russian experts, use a simpler principle for determining the prognosis of AML after relapse occurs: if the relapse is early (CR duration less than 12 months), the prognosis is unfavorable; if late (CR duration 12 months or more), the prognosis is more favorable [8]. Both approaches (the prognostic index and the classification of relapses into early and late) are used in Russian research centers.

Comment: high-dose cytarabine** therapy (if not used in the 1st line induction) combined with anthracyclines and related compounds may be considered as remission induction prior to allo-HSCT. To improve HSCT outcomes in patients with refractory AML, conditioning regimens are used—sequential administration of intensive chemotherapy followed 3 days later by a reduced-intensity conditioning regimen followed by allo-HSCT (the so-called FLAMSA-RIC protocol) and subsequently prophylactic donor lymphocyte infusions and/or azacitidine** therapy.

Comment: repeating the induction chemotherapy course is advisable if the number of blast cells in the myelogram decreases by 25% compared to baseline values. In case of disease progression (persistence of the previous percentage or increase in blast cells, appearance of previously undetected extramedullary foci), it is advisable to administer high-dose cytarabine** chemotherapy combined with novel anthracyclines and related compounds as the 2nd induction course (see Appendix A3.1).

In some cases, non-intensive therapy with low-dose #cytarabine** (10 mg/m² twice daily s.c.) either as monotherapy (28 days) or combined with low doses of anthracyclines and related compounds (in particular, idarubicin**) with a hypomethylating pre-phase (Dec-Ida-Ara-c), or venetoclax** therapy combined with pyrimidine analogues (see Appendix A3.1) can be used as 2nd-line AML therapy: 1) in patients who cannot tolerate a high-dose approach due to comorbidities or age; 2) in patients with acute erythroblastic and megakaryoblastic leukemias who fail to achieve CR on standard courses; 3) in patients from the adverse molecular-genetic risk group.

Comment: these patients are candidates for enrollment in clinical trials investigating new drugs.

Comment: the classic choice is the repetition of the 1st induction regimen (see Appendix A3.1). A combination of standard-dose cytarabine** (100 mg/m² every 12 h for 7 consecutive days or 200 mg/m² per day continuously on days 1–7) and idarubicin** (12 mg/m² once daily on days 1–3) can also be used. The chances of achieving a 2nd CR are quite high (~70%).

Comment: for patients with expected excessive chemotherapy toxicity, low-intensity treatment regimens are a possible option (see Appendix A3.1).

Comment: if allo-HSCT is not feasible (e.g., due to the lack of a suitable donor), auto-HSCT may be considered as 2nd-line therapy, but its efficacy is not clearly defined.

Comment: 2 induction courses are administered and, if CR is achieved, another 2 consolidation courses. Subsequently, maintenance therapy is continuously carried out for 3 years using similar regimens without idarubicin**.

Comment: Response to gilteritinib monotherapy may be delayed, meaning it can take up to 6 months of using the drug at the prescribed dose to achieve a clinical response. If there is no response after 4 weeks of therapy, the dose may be increased to 200 mg once daily. Upon achieving a second remission and if HSCT is not feasible, therapy should be continued for 2 years. In patients who have undergone hematopoietic stem cell transplantation, treatment with gilteritinib may be resumed after donor hematopoiesis recovery. Administration of gilteritinib is recommended to be continued for 2 years. In case of complications, the daily dose of gilteritinib may be reduced from 120 mg to 80 mg or from 200 mg to 120 mg. Treatment with gilteritinib should be interrupted if toxicity symptoms of grade 3 or higher associated with its use appear. Once toxic events resolve or improve to grade 1 severity, resume the use of the drug at a lower dose.

Comment: in case of complications, the drugs are temporarily discontinued and resumed after 2–3 weeks at a reduced dosage, followed by a gradual return to the therapeutic dose.

Comment: patients with a late relapse (more than 1 year after allo-HSCT) may undergo a 2nd allo-HSCT after achieving a secondary remission.

3.4. Management of patients in special clinical situations

3.4.1. Acute myeloid leukemia with hyperleukocytosis

Comment: hyperleukocytosis is generally defined as a leukocyte count ˃100*10⁹/L, and this condition is naturally associated with increased induction mortality due to hemorrhagic complications, tumor lysis syndrome, and infectious complications [1].

If there are obvious signs of "leukostasis" against the background of hyperleukocytosis (˃100*10⁹/L), along with the administration of #hydroxycarbamide**, it is advisable to perform 2–3 sessions of leukocytapheresis. If signs of tumor lysis syndrome appear against the background of cytolytic syndrome, it is recommended to perform small-volume plasmapheresis (1–1.2 L) with replacement by human albumin** and plasma to prevent acute respiratory distress syndrome and acute renal failure. To avoid "massive" cytolysis in this situation, one can first administer cytarabine** alone and then perform plasmapheresis, while postponing the administration of daunorubicin** to days 5–7 of the course, or performing plasmapheresis on the first days of the course 2–3 hours after the administration of cytarabine** or interrupting the continuous infusion of cytarabine** for the duration of the procedure. If gemtuzumab ozogamicin is included in the treatment regimen, the administration of the drug is postponed to days 3, 6, and 9 of the course. If a single administration of gemtuzumab ozogamicin is scheduled, it is postponed to the last day of the "7+3" course. A detailed therapeutic algorithm for remission induction in AML patients with initial hyperleukocytosis is provided in Appendix A3.2.

3.4.2. Myeloid sarcoma

Comment: neuroprophylaxis is indicated for myeloid sarcoma. Myeloid sarcoma (synonyms: extramedullary myeloid tumor, granulocytic sarcoma, chloroma) is a tumor composed of myeloid precursor cells arising anywhere outside the bone marrow (most commonly in the skin, lymph nodes, gastrointestinal tract, bones, soft tissues, and testes). Myeloid sarcoma may develop de novo preceding AML, occur concurrently with AML development, or present as blastic transformation of MDS, MPN, or MDS/MPN. The diagnosis is established based on a tumor biopsy followed by cytochemical (touch imprints) and immunohistochemical (biopsy specimen) methods [1].

3.4.3. Treatment of acute myeloid leukemia during pregnancy

Treatment of AML during pregnancy is carried out in a hospital setting by a multidisciplinary team of physicians, including a hematologist, obstetrician-gynecologist, and anesthesiologist-resuscitologist, with the capacity to provide obstetric care and delivery in emergency situations [111].

Comment: if the woman and her family insist on continuing the pregnancy, treatment may be initiated in the first trimester as well.

Comment: in the presence of hyperleukocytosis, delivery is performed during cytoreductive therapy.

Comment: antitumor drugs are calculated according to the selected treatment regimen (without dose reduction) based on the patient's pre-pregnancy body surface area, with weight-based adjustments during treatment. In life-threatening maternal complications, systemic antibacterial drugs may be prescribed without regard to their potential teratogenic effects on the fetus.

GCP CLoE 5Grading of Recommendations Assessment, Development and Evaluation (GRADE) – C (Level of Evidence – 5)

Comment: the choice of delivery method is determined by the fetal condition, somatic status of the patient, hematological parameters, and strictly in accordance with obstetric indications. Vaginal delivery may be chosen as the mode of delivery only if the patient is in AML remission, has satisfactory hemogram parameters, and good somatic status of both the patient and the fetus.

3.5. Supportive Care

Comment: patients who were diagnosed with invasive aspergillosis during previous chemotherapy courses should receive secondary antifungal prophylaxis using the drug with which cure of invasive aspergillosis was achieved. In most cases, voriconazole** is used for this purpose.

Comment: modification of antimicrobial therapy is carried out in accordance with the findings of the diagnostic work-up (CT, microbiological studies, etc.). The administration of carbapenems as first-line drugs for febrile neutropenia is justified in patients with septic shock, as well as in clinics where extended-spectrum beta-lactamase-producing Enterobacteriaceae predominate in the etiology of infections.

Comment: any manifestation of hemorrhagic syndrome (petechial rashes, especially on the oral mucosa, face, and anterior chest wall, any bleeding) and/or a body temperature rise above 37.5 °C, even in the absence of an obvious infection focus, require platelet concentrate transfusions even if the peripheral blood platelet count is ˃20*10⁹/L. Similar indications apply to platelet concentrate transfusions when preparing a patient for invasive procedures.

Comment: indications and volume of transfusion support are determined by coagulogram parameters and the clinical situation.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

There are no special rehabilitation methods for AML.

Comment: polychemotherapy can cause cardiotoxicity, hepatotoxicity, neurotoxicity, nephrotoxicity, and other toxicities, the consequences of which may persist even after its completion. After treatment completion, patients should maintain a healthy lifestyle and avoid sun exposure and physiotherapy procedures.

5. Prevention and Dispensary Observation

There is no specific prevention for AML.

Comment: unscheduled hemogram testing is indicated for any changes in the patient's condition. Unscheduled bone marrow testing is indicated upon detecting any hemogram abnormalities. Most relapses occur within 1–3 years after treatment completion. Standardized time points for bone marrow aspiration are essential for MRD monitoring.

6. Organization of Medical Care

Medical care, with the exception of medical care within the framework of clinical approbation, in accordance with Federal Law No. 323-FZ dated November 21, 2011 (as amended on August 8, 2024) "On the Fundamentals of Protecting the Health of Citizens in the Russian Federation", is organized and provided:

1. in accordance with the regulations on the organization of medical care by types of medical care, which is approved by the authorized federal executive body;

2. in accordance with the procedure for the provision of care for the profile "hematology", mandatory for execution on the territory of the Russian Federation by all medical organizations;

3. based on these clinical guidelines;

4. taking into account the standards of medical care approved by the authorized federal executive body.

Primary specialized health care is provided by a hematologist and other medical specialists at an ambulatory hematology/oncology care center, a primary hematology/oncology office, a primary hematology department, or an outpatient department of an oncological dispensary.

If AML is diagnosed or suspected, general practitioners, district general practitioners, general family physicians, specialist physicians, and mid-level medical personnel shall refer the patient in the established manner for consultation to an outpatient hematology/oncology center or a primary hematology office or primary hematology department of a medical organization to receive primary specialized health care.

An outpatient or inpatient hematologist organizes the diagnostic tests necessary to establish the diagnosis, including disease extent and stage.

If diagnostic examinations cannot be performed, the attending physician refers the patient to a medical organization providing medical care to patients with hematological diseases to establish a diagnosis and provide specialized, including high-tech, medical care.

If AML is detected or suspected during the provision of emergency medical care, the patient is transferred or referred to medical organizations that provide medical care to patients with hematological diseases to determine the management strategy and the need for additional specialized antineoplastic treatment methods.

Specialized, including high-tech, medical care is provided by hematologists in medical organizations that provide medical care to patients with AML, which have a license, the necessary material and technical base, and certified specialists, in inpatient and day hospital settings, and includes the prevention, diagnosis, and treatment of hematological diseases requiring the use of special methods and complex unique medical technologies, as well as medical rehabilitation.

In a medical organization providing medical care to patients with AML, the medical examination and treatment strategy is established by hematologists, involving other medical specialists if necessary, and through a medical panel (consilium) if required. The decision of the medical panel is formalized in a protocol, signed by the participating physicians, and entered into the patient's medical documentation.

Indications for hospitalization in a 24-hour or day hospital of a medical organization providing specialized, including high-tech, medical care in the specialty "hematology" are determined by a hematologist/medical panel with the involvement of other medical specialists if necessary.

Indications for planned hospitalization:

• suspension/establishment of an acute leukemia diagnosis;

• diagnosis of AML relapse;

• administration of a regular course of chemotherapy in a 24-hour or day hospital setting;

• performance of planned hematopoietic stem cell transplantation (HSCT);

• performance of elective surgical interventions;

• performance of elective extracorporeal blood purification methods and renal replacement therapy;

• administration of replacement blood component therapy.

Indications for emergency hospitalization:

• emergency conditions in patients with AML and suspected acute leukemia:

• leukocytosis ˃100×10⁹/L;

• febrile neutropenia and infectious complications against the background of neutropenia after a course of chemotherapy;

• hemorrhagic syndrome;

• thrombotic complications;

• need for emergency replacement blood component therapy;

• other systemic disorders caused by the underlying disease or developed as a result of the treatment administered.

Indications for patient discharge from the hospital:

• restoration of peripheral blood parameters (leukocyte count ˃1×10⁹/L, granulocyte count ˃0.5×10⁹/L, platelet count ˃50×10⁹/L, hemoglobin ˃80 g/L) after a regular course of chemotherapy;

• normothermia for 3–5 days and the absence of uncontrolled infectious complications in the post-course period;

• relief of hemorrhagic complications;

• relief of thrombotic complications;

• relief of systemic disorders caused by the course of the underlying disease or developed as a result of the treatment administered.

The conclusion on the advisability of transferring a patient to a specialized medical organization is made after a preliminary consultation on the provided medical documents and/or a preliminary examination of the patient by specialist physicians of the medical organization to which the transfer is planned.

7. Additional Information

7.1 Prevention, diagnosis, and treatment of hemorrhagic complications in patients with leukemia

Hemorrhagic manifestations in patients with AML are diverse and may be caused by both the disease itself and its complications, including as a result of specific therapy, and may also appear as a result of ongoing antithrombotic therapy. Hemorrhagic manifestations can occur at any stage of diagnosis and treatment of AML. To prevent hemorrhagic disorders, dynamic laboratory monitoring of peripheral blood parameters and coagulogram, as well as timely instrumental studies, are required [124, 125-127].

Features of the diagnosis and treatment of hemorrhagic syndrome in AML patients are described in the section "Prevention, diagnosis, and treatment of hemorrhagic and thrombotic complications in patients with hematological diseases" of the guide "Supportive therapy in the treatment of diseases of the blood system" [128].

7.2 Prevention, diagnosis, and treatment of thrombotic complications

In leukemias, both initially and during their chemotherapy and other treatments, thrombotic complications often occur, requiring prevention and therapy. The frequency of thrombotic disorders in blood system tumors varies; chemotherapy increases the frequency of thrombotic complications almost 2-fold, from 2.21% to 4.24% relative to the baseline level [124, 129-134].

Features of the diagnosis and treatment of hemorrhagic syndrome in AML patients are described in the section "Prevention, diagnosis, and treatment of hemorrhagic and thrombotic complications in patients with hematological diseases" of the guide "Supportive therapy in the treatment of diseases of the blood system" [128].

7.3 Prevention and treatment of cardiac complications in patients with leukemia

The experience of long-term observation and treatment of patients with leukemias shows that cardiological problems not only affect the choice of hematological therapy and the possibility of its continuation, but also significantly affect the quality and duration of life; therefore, issues of supportive cardiological management in hematological practice are extremely relevant and important [129-138].

Features of the diagnosis and treatment of cardiac pathology in AML patients are described in the section "Supportive therapy in patients with hematological diseases" of the guide "Supportive therapy in the treatment of diseases of the blood system" [139].

7.4 Diagnosis and treatment of neurological manifestations in leukemia

Neurological manifestations involving the central nervous system (CNS) and peripheral nervous system can be either a manifestation of specific nervous system involvement (tumor involvement of the CNS) or a manifestation of complications of leukemia and its treatment (hemorrhagic, thrombotic, toxic lesions of the nervous system). For the diagnosis and treatment of neurological manifestations and complications in leukemia, a set of neurological examinations and therapy appropriate to the type of disorder, taking into account the nature of the underlying hematological disease, are used [140-146].

Features of the diagnosis and treatment of neurological pathology in AML patients are described in the section "Supportive therapy in patients with hematological diseases" of the guide "Supportive therapy in the treatment of diseases of the blood system" [147].

7.5 Diagnosis and treatment of infectious complications

Infections are leading complications in the treatment of blood system diseases. The highest incidence is observed in patients with acute leukemias and recipients of allogeneic hematopoietic stem cells (allo-HSCT), ranging from 30 to 90%. Thus, in patients with acute myeloid leukemias, infectious complications account for 80-90% during the induction and consolidation of remission stages; in allogeneic HSCT recipients, during the granulocytopenia period at the stage of hematopoietic cell engraftment (40-70%) and during the development of graft-versus-host disease (10-70%). The frequency of infectious complications is higher during remission induction, in the resistant variant of the tumor, during high-dose chemotherapy, with concomitant hypogammaglobulinemia, and during periods of forced hypodynamia and constant bed rest.

The main factor determining the development of infectious complications in hematological patients is neutropenia (neutrophils <0.5x10⁹/L) or leukopenia (leukocytes ≤1 000x10⁹/L), as well as the duration of neutropenia—the frequency of infections increases significantly when neutropenia lasts longer than 10 days. In addition to bacterial infections, viral infections also frequently develop [29, 45, 148-155]. Furthermore, the characteristics of immunodeficiency in patients with leukemias are associated with an increased incidence of opportunistic infections, primarily infectious complications caused by fungi [150, 151, 156-163].

Features of the diagnosis, prevention, and treatment of infectious complications in AML patients are described in the section "Prevention, diagnosis, and treatment of infectious

7.6 Diagnosis and treatment of pain syndrome in AML patients

The International Association for the Study of Pain (IASP) defines pain as an unpleasant sensory or emotional experience associated with actual or potential tissue damage, or described in terms of such damage [122, 164–168]. Pain often causes severe suffering and has a significant impact on the quality of life of the patient and their family. Pain in hematological patients is quite common: it can be a manifestation of the severe illness itself or a complication of treatment. Effective pain therapy requires determining its cause, intensity, and type.

Features of the diagnosis and treatment of pain syndrome in AML patients are described in the section "Supportive therapy in patients with hematological diseases" of the guide "Supportive therapy in the treatment of diseases of the blood system" [169].

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Al-Radhi L.S., PhD, Senior Research Fellow, Clinical and Diagnostic Department of Hematology and Chemotherapy with Day Hospital, National Medical Research Center for Hematology of the Russian Ministry of Health, Member of the National Hematological Society.

2. Baranova O.Yu., PhD, Senior Research Fellow, Bone Marrow Transplantation Department, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, Moscow, Member of the National Hematological Society.

3. Bondarenko S.N., PhD, Head of the Department of Oncology, Hematology and Transplantology for Adolescents and Adults, R.M. Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, First Saint Petersburg State Pavlov Medical University of the Russian Ministry of Health, Member of the National Hematological Society.

4. Gaponova T.V., PhD, Chief freelance transfusionist of the Russian Ministry of Health, First Deputy General Director, National Medical Research Center for Hematology of the Russian Ministry of Health, Member of the National Hematological Society.

5. Kashlakova A.I., Hematologist, Department of Chemotherapy of Hemoblastoses and Hematopoietic Depressions with Bone Marrow and Hematopoietic Stem Cell Transplantation Unit, National Medical Research Center for Hematology of the Russian Ministry of Health, Member of the National Hematological Society

6. Kaplanov K.D., MD, Head of Hematology Department No. 11, Botkin City Clinical Hospital of the Moscow Healthcare Department

7. Kaporskaya T.S., PhD, Head of the Hematology Department, Irkutsk Order of the Badge of Honour Regional Clinical Hospital, Member of the National Hematological Society.

8. Klyasova G.A., MD, Professor, Head of the Laboratory of Clinical Bacteriology, Mycology and Antibiotic Therapy, National Medical Research Center for Hematology of the Russian Ministry of Health, Member of the National Hematological Society.

9. Konstantinova T.S., PhD, Sverdlovsk Regional Hematological Center of the Sverdlovsk Regional Clinical Hospital No. 1, Member of the National Hematological Society.

10. Kuzmina L.A., PhD, Head of the Department of Intensive High-Dose Chemotherapy and Bone Marrow Transplantation with 24-hour Inpatient Unit, National Medical Research Center for Hematology of the Russian Ministry of Health, Member of the National Hematological Society.

11. Lapin V.A., PhD, Head of the Hematology Department, Yaroslavl Regional Clinical Hospital, Member of the National Hematological Society.

12. Lukyanova I.A., PhD, Head of the Day Hospital for Oncology and Chemotherapy of Hemoblastoses and Hematopoietic Depressions, National Medical Research Center for Hematology of the Russian Ministry of Health, Member of the National Hematological Society.

13. Parovichnikova E.N., MD, Chief freelance hematologist of the Russian Ministry of Health, General Director, National Medical Research Center for Hematology of the Russian Ministry of Health, Member of the National Hematological Society.

14. Ptushkin V.V., MD, Professor, Chief freelance hematologist of the Moscow Healthcare Department, Deputy Chief Medical Officer for Hematology, Botkin City Clinical Hospital of the Moscow Healthcare Department

15. Savchenko V.G., Academician of the Russian Academy of Sciences, MD, Professor

16. Samoylova O.S., PhD, Head of the Hematology Department, N.A. Semashko Nizhny Novgorod Regional Clinical Hospital, Member of the National Hematological Society.

17. Semochkin S.V., MD, PhD, Professor at the Department of Oncology, Hematology and Radiology, Pirogov Russian National Research Medical University of the Russian Ministry of Health, Member of the National Hematological Society.

18. Sokolov A.N., PhD, Senior Researcher at the Department of Chemotherapy for Hemoblastoses, Hematopoietic Depressions and Bone Marrow Transplantation, National Research Center for Hematology of the Russian Ministry of Health, Member of the National Hematological Society.

19. Troitskaya V.V., MD, PhD, First Deputy General Director, National Research Center for Hematology of the Russian Ministry of Health, Member of the National Hematological Society.

    • Allogeneic Hematopoietic Stem Cell Transplantation Section

20. Drokov M.Yu., PhD, Head of the Sector for the Study of Immune Effects and Complications Post-BMT, National Research Center for Hematology of the Russian Ministry of Health

21. Vasilyeva V.A., PhD, Head of the Department of Immunochemotherapy with a Day Hospital for Post-BMT Patients, National Research Center for Hematology of the Russian Ministry of Health

22. Vlasova Yu.Yu., PhD, Head of the Adult Bone Marrow Transplantation Department, Research Institute of Pediatric Oncology, Hematology and Transplantology, Academician I.P. Pavlov First Saint Petersburg State Medical University of the Ministry of Health of the Russian Federation

23. Zaritskiy A.Yu., MD, PhD, Professor

24. Zyuzgin I.S., Head of the Department of Hematology and Bone Marrow Transplantation, N.N. Petrov National Medical Research Center of Oncology of the Russian Ministry of Health

25. Kulagin A.D., MD, PhD, Director of the Research Institute of Pediatric Oncology, Hematology and Transplantology, Academician I.P. Pavlov First Saint Petersburg State Medical University of the Ministry of Health of the Russian Federation,

26. Minayeva N.V., Deputy Director for Clinical Work, Kirov Research Institute of Hematology and Blood Transfusion of the Federal Medical-Biological Agency of Russia

27. Moiseev I.S., MD, PhD, Deputy Director for Science, Research Institute of Pediatric Oncology, Hematology and Transplantology, Academician I.P. Pavlov First Saint Petersburg State Medical University of the Ministry of Health of the Russian Federation

28. Morozova E.V., PhD, Head of the Department of Adult Hematology, Oncology and Transplantation, Research Institute of Pediatric Oncology, Hematology and Transplantology, Academician I.P. Pavlov First Saint Petersburg State Medical University of the Ministry of Health of the Russian Federation

29. Petrova G.D., PhD, Head of the Department of Bone Marrow and Hematopoietic Stem Cell Transplantation, Department of Hematology and Bone Marrow Transplantation, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health,

30. Popova M.O., PhD, Associate Professor at the Department of Hematology, Transfusiology and Transplantology, Faculty of Postgraduate Education, Academician I.P. Pavlov First St. Petersburg State Medical University

31. Estrina M.A., PhD, Head of the Clinical Transfusiology Department, Research Institute of Pediatric Oncology, Hematology and Transplantology, Academician I.P. Pavlov First Saint Petersburg State Medical University of the Ministry of Health of the Russian Federation

No conflicts of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience of the clinical guidelines:

• hematologists;

• oncologists;

• general practitioners (internal medicine);

• obstetricians-gynecologists;

• anesthesiologists-intensivists;

• clinical pharmacologists.

Methodology for evidence collection. Methods used for collecting/selecting evidence:

• search for publications in specialized peer-reviewed periodicals;

• electronic database searching.

Databases used for evidence collection/selection. The evidence base for the guidelines includes publications indexed in the Cochrane Library, PubMed, and MedLine databases. The search depth was 30 years.

Methods used for evidence analysis:

• reviews of published meta-analyses;

• systematic reviews with evidence tables.

Methods used for assessing the quality and strength of evidence:

• expert consensus;

• evaluation of the significance of evidence in accordance with the evidence rating scheme (Tables 2–4).

Table 2. Scale for assessing levels of evidence (LE) for diagnostic methods (diagnostic interventions)

Table 3. Scale for assessing levels of evidence (LE) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Table 4. Scale for assessing grades of recommendation (GR) for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines.

Updating is carried out at least once every 3 years, taking into account new information on the diagnosis and management of patients with AML, but no more frequently than once every 6 months. The decision to update is made by the Russian Ministry of Health based on proposals submitted by professional medical non-profit organizations. The formulated proposals must take into account the results of comprehensive assessments of medicinal products and medical devices, as well as the results of clinical approbation.

Appendix A3. Reference Materials

Appendix A3.1. Chemotherapy regimens for AML

Table 1. Remission induction and consolidation regimens for AML

Table 2. Treatment regimens for refractory and relapsed AML used by various study groups

Table 3. Maintenance therapy regimens

Table 4. Non-intensive induction and remission consolidation regimens for elderly AML patients or patients ineligible for intensive therapy

Appendix A3.2. Induction phase protocol for AML with hyperleukocytosis

Hyperleukocytosis in AML is a medical emergency associated with severe, life-threatening complications that requires immediate specialized therapeutic interventions.

Factors associated with hyperleukocytosis in AML are presented in Table 1.

Treatment algorithm for the induction of remission in AML presenting with hyperleukocytosis [185, 186].

• Chemotherapy is carried out according to the protocols established for specific disease variants, in accordance with the patient's age and the immunophenotype/genotype of the tumor cells.

• Central venous catheter placement is mandatory prior to the initiation of induction therapy.

• To treat hyperuricemia, allopurinol** is prescribed in doses according to the product labeling [98, 187].

• From the first day of the course, the fluid intake is increased to 1.5–2.0 L/m² per day (dextrose** and sodium chloride** solutions in a 1:1 ratio). In cases of high tumor burden (including organomegaly), the fluid volume (including all transfused blood products) may be increased to 3 L/m² with diuresis stimulation using diuretics, mandatory monitoring of urine output, and central venous pressure (CVP).

Leukostasis syndrome is diagnosed prior to chemotherapy in AML patients regardless of the leukocyte count (it can also manifest at leukocyte counts below 100 × 10⁹/L) if lethargy, somnolence, inability to concentrate, respiratory failure, severe coagulation disorders, severe hemorrhagic syndrome not directly related to thrombocytopenia, or metabolic disorders are detected.

• In AML with significant leukocytosis (above 70 × 10⁹/L), #hydroxycarbamide** must be prescribed at a dose of 50–75 mg/kg/day (the dose may be increased up to 150 mg/kg/day if necessary) [188].

If the leukemia variant has not yet been determined, #hydroxycarbamide** may be recommended at a dose of 50–75 mg/kg/day (in 3–4 divided doses) until the acute leukemia variant is diagnosed (hydroxycarbamide** is not indicated if APL is suspected). The chemotherapy course may be started once leukocytosis decreases to 50–70 × 10⁹/L.

• If there are clear signs of leukostasis (confused state, interstitial lung lesions due to a vascular component, dyspnea), alongside mandatory #hydroxycarbamide** administration and volume loading, 1–2 sessions of leukocytapheresis should be performed for rapid tumor mass reduction [188, 189].

If the leukocyte count is greater than 100×10⁹/L, but less than 150×10⁹/L and there is no leukostasis syndrome, leukapheresis may be omitted. If the leukocyte count in patients with acute myeloid leukemia exceeds 150×109/L, leukapheresis can be considered a necessary procedure in combination with all other methods of cytoreduction and prevention/treatment of tumor lysis syndrome.

• If the tumor volume decreases by 30–40% after the first leukocytapheresis session (leukocyte count below 100 × 10⁹/L), initiating chemotherapy is indicated [190].

The treatment plan must include plasmapheresis in a volume of 0.8–1.5 L after the administration of antineoplastic agents. In this situation, it is advisable to administer cytarabine** first and perform plasmapheresis, while delaying the administration of anthracyclines and related compounds to days 3–5 or 5–7, performing plasmapheresis on the first two to three days during cytarabine** administration. Since the clearance of cytarabine** is very high, plasmapheresis will not affect its plasma concentration; at the same time, plasmapheresis may affect the concentration of anthracyclines and related compounds, which have a fairly long half-life.

• During plasmapheresis in cases of continuous cytarabine** infusion, the drug administration must be interrupted and resumed after the procedure, recalculating the infusion rate for the remaining time within the 24-hour infusion period.

If cytarabine** is administered twice daily, the plasmapheresis procedure is performed 3–4 hours after drug administration.

• Plasmapheresis may also be performed at lower leukocyte counts if tumor lysis syndrome develops during antineoplastic therapy: high fever, respiratory failure, signs of hepatic and renal failure, lethargy, impaired consciousness, worsening hemorrhagic syndrome, etc.

• During hyperleukocytosis therapy, the following laboratory and instrumental tests must be performed:

  • complete blood count (CBC) (during hyperleukocytosis therapy — twice daily);

  • coagulogram (screening test of the hemostatic system) — during the first week, 1–2 times daily;

  • general clinical blood chemistry (total blood protein, protein fraction ratio by electrophoresis, blood urea nitrogen, creatinine, total bilirubin, sodium, potassium, total calcium, blood glucose, alanine aminotransferase, aspartate aminotransferase, serum total magnesium) – daily;

  • study of acid-base balance and blood gases;

  • computed tomography of the chest cavity;

  • computed tomography of the brain.

• If acute kidney injury develops during hyperleukocytosis and tumor lysis therapy, hemodialysis must be performed until renal function is fully recovered.

Hemodialysis is not a contraindication to initiating or completing planned chemotherapy. The presence of hyperleukocytosis at the onset of acute leukemia in most cases implies the presence of neuroleukemia, which requires an increased number of lumbar punctures with intrathecal administration of a standard drug set.

• Diagnosis of hemostatic disorders in acute leukemia with hyperleukocytosis should include both conventional coagulation assays and viscoelastic (integral) tests. Hypofibrinogenemia is one of the frequent disorders.

• Patients with AML presenting with hyperleukocytosis, alongside all therapeutic measures, are indicated for massive platelet transfusions (a single infusion should comprise 8–10 doses).

Low hemoglobin, platelet, and albumin levels should not be considered a contraindication to plasmapheresis, but the procedure must be supported by an adequate volume of replacement therapy (transfusions of packed red blood cells, platelet concentrate, human albumin**, fresh frozen plasma).

Appendix B. Physician Action Algorithms

Fig. 1. Standard algorithm for treatment selection in a patient with AML under 60 years of age

Fig. 2. Standard algorithm for treatment selection in a patient with AML over 60 years of age

Appendix C. Patient Information

Acute myeloid leukemia (AML) is also referred to as acute myelogenous leukemia and acute nonlymphocytic leukemia. AML develops when a DNA mutation occurs in immature bone marrow cells. The exact cause of AML is unknown. AML can occur at any age and is the most common form of acute leukemia in adults. AML causes the uncontrolled proliferation of blast cells—immature cells of the blood and bone marrow that cannot function normally. Patients with AML have a reduced count of mature, healthy blood cells of all types: erythrocytes, platelets, and leukocytes. Depending on the predominant cell type affected, AML is classified into several subtypes. A definitive diagnosis is established following examination of blood and bone marrow samples. Treatment selection for AML depends on the disease subtype and other factors, such as the presence and type of chromosomal abnormalities. AML symptoms also vary depending on the disease subtype. Patients with a low erythrocyte count exhibit classic symptoms of anemia: rapid fatigue, shortness of breath, and pallor. Patients with a low platelet count may experience prolonged bleeding and easy bruising.

Patients with AML almost always receive chemotherapy, which begins immediately after diagnosis. The goal of this treatment, known as induction therapy, is to achieve remission and restore normal hematopoiesis. Remission of acute leukemia is the resolution of pathological manifestations of the process under the influence of antileukemic therapy. Chemotherapy is highly intensive and affects not only malignant but also healthy blood cells; as a result, patients receiving induction therapy may suffer from various side effects, such as nausea, fatigue, and increased susceptibility to infections. In most patients, normal hematopoiesis recovers within a few weeks after induction therapy, and AML remission is confirmed. At this point, a decision is made regarding further treatment methods. This may include continuation of chemotherapy for consolidation of remission aimed at more complete eradication of leukemic cells, or maintenance therapy.

Another treatment method is allogeneic hematopoietic stem cell transplantation (allo-HSCT). Currently, the source of hematopoietic stem cells (immature precursor cells from which the three blood cell types—leukocytes, erythrocytes, and platelets—ultimately develop) can be bone marrow, umbilical cord blood, or peripheral blood from a donor. Regardless of the source, stem cells are administered intravenously into the patient's body following high-dose chemotherapy or radiation therapy designed to completely eradicate the patient's leukemic cells. Pre-transplant conditioning chemotherapy also destroys the patient's immune system, which the infused donor cells must subsequently reconstitute.

Allogeneic transplantation requires a related or unrelated donor who is HLA-matched with the patient. A related donor is usually a sibling. If a related donor is not found, the physician searches the databases of Russian and/or international donor registries. Regardless of whether a related or unrelated donor is found, the transplantation procedure is the same: donor hematopoietic stem cells are harvested and then administered intravenously to the patient.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Appendix G1. Molecular genetic classification of acute myeloid leukemias

Russian title: European LeukemiaNet (ELN) genetic risk classification for AML (2017)

Original title: 2017 ELN risk stratification by genetics

Source (developer's official website, validation publication): Döhner H., Estey E., Grimwade D. et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood 2017; 129(4):424–47 [8]

Type: rating scale

Purpose: prognostic evaluation of the patient's condition

Content and interpretation:

Notes:

*Low allelic ratio (<0.5).

**High allelic ratio (≥0.5).

***If these mutations are detected in patients with favorable cytogenetic abnormalities, their presence carries no prognostic significance.

Appendix G2. Molecular genetic classification of acute myeloid leukemias

Russian title: European LeukemiaNet 2022 genetic risk stratification for acute myeloid leukemias (European LeukemiaNet, ELN 2022)

Original title: 2022 European LeukemiaNet (ELN) risk classification by genetics at initial diagnosis

Source (developer's official website, validation publication): Döhner H, Wei AH, Appelbaum FR et al. Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN. Blood 2022; 140(12):1345—1377. DOI:10.1182/blood.2022016867.

Type: rating scale

Purpose: determination of patient disease prognosis

Content and interpretation:

Appendix G3. ECOG performance status scale

Russian title: Eastern Cooperative Oncology Group Performance Status Scale

Original title: The ECOG Scale of Performance Status

Source (developer's official website, validation publication): Oken M.M. et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group // Am. J. Clin. Oncol. 1982. Vol. 5, № 6. P. 649–65 [11]

Type: rating scale

Purpose: clinical assessment of the patient's general condition

Content and interpretation:

Appendix G4. Risk factors associated with transplant-related mortality

Russian title: Risk factors associated with transplant-related mortality

Original title: Prognostic factors for allogeneic-HSCT-related nonrelapse mortality

Source (developer's official website, validation publication): Cornelissen, J., Gratwohl, A., Schlenk, R. et al. The European LeukemiaNet AML Working Party consensus statement on allogeneic HSCT for patients with AML in remission: an integrated-risk adapted approach. Nat Rev Clin Oncol 9, 579–590 (2012) doi: 10.1038/nrclinonc.2012.150

Type: rating scale

Purpose: prognostic evaluation of the patient's condition

Content and interpretation:

Appendix G5. Prognostic index for young patients with relapsed acute myeloid leukemia

Russian title: Prognostic index for young patients with relapsed acute myeloid leukemia

Original title: European Prognostic Score for acute myeloid leukaemia at first relapse.

Source (official developer website, validation publication): Giles F., Verstovsek S., Garcia-Manero G. et al. Validation of the European Prognostic Index for younger adult patients with acute myeloid leukaemia in first relapse. Br J Haematol 2006; 134(1):58–60 [69].

Type: index

Purpose: Prognostic index for young patients with relapsed AML (15–60 years, excluding acute promyelocytic leukemia t(15;17))

Content and interpretation:

Calculated according to the following factors:

• remission duration prior to relapse: 18 months – 0 points, 7–17 months – 3 points, ≤6 months – 5 points;

• cytogenetic abnormalities at initial diagnosis: inv(16) or t(16;16) – 0 points, t(8;21) – 3 points, others – 5 points;

• prior HSCT: no – 0 points, yes – 2 points;

• age at relapse: 35 years or younger – 0 points, 36–45 years – 1 point, older than 45 years – 2 points.