Myelodysplastic syndrome. Myelodysplastic/myeloproliferative neoplasms: clinical guidelines

List of Abbreviations

allo-HSCT – allogeneic hematopoietic stem cell transplantation

ALT – alanine aminotransferase

anti-DNA – anti-DNA antibodies

ASLO – antistreptolysin O

AST – aspartate aminotransferase

ATG – antithymocyte globulin**

anti-TPO – anti-thyroid peroxidase antibodies

aCML – atypical chronic myeloid leukemia

ANC – absolute neutrophil count

aPTT – activated partial thromboplastin time

ESBL – extended-spectrum beta-lactamases

HIV – human immunodeficiency virus

WHO – World Health Organization

HIF – hypoxia-inducible factor

G-CSF – granulocyte colony-stimulating factor (ATC: L03AA – colony-stimulating factors: filgrastim**,

HMA – hypomethylating agents (ATC: L01BC - pyrimidine analogues: azacitidine**, decitabine, cytarabine**)

HSC – Hematopoietic Stem Cells

DNA – deoxyribonucleic acid

GI – gastrointestinal tract

EB-1 – excess blasts-1

EB-2 – excess blasts-2

IHC – immunohistochemical methods

BMI – body mass index

IST – immunosuppressive therapy

CT – clinical trials

BM – bone marrow

RS – ring sideroblasts

CT – computed tomography

SLD – single lineage dysplasia

LDH – lactate dehydrogenase

MLD – multilineage dysplasia

MDS — myelodysplastic syndrome

MDS/MPN – myelodysplastic/myeloproliferative neoplasm

MDS/MPN-RS-T – myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis

MDS/MPN-U – myelodysplastic/myeloproliferative neoplasm, unclassifiable

MDS-5q – MDS with isolated deletion of the long arm of chromosome 5

MDS-U – myelodysplastic syndrome, unclassifiable

LD-Ara-C – low-dose #cytarabine**

MRD – minimal residual disease

MRI – magnetic resonance imaging

OS – overall survival

AL – acute leukemia

ALL – acute lymphoblastic leukemia

AML – acute myeloid leukemia

PB – peripheral blood

PNH — paroxysmal nocturnal hemoglobinuria

CR – complete remission

PCT – polychemotherapy

PCR – polymerase chain reaction

CRP – C-reactive protein

T3 – triiodothyronine

fT4 – free thyroxine

BMT – bone marrow transplantation

TSH – thyroid-stimulating hormone

LCE – level of confidence of evidence

US – ultrasound examination

LOR – level of recommendation

CT – chemotherapy

CMML – chronic myelomonocytic leukemia

CNS – central nervous system

CsA – #cyclosporine**

PR – partial remission

EBV – Epstein–Barr virus

EGD – esophagogastroduodenoscopy

ECG – electrocardiography

sEPO – serum erythropoietin

ESAs – erythropoiesis-stimulating agents (ATC: B03X - other antianemic preparations: epoetin alfa**, epoetin beta**, darbepoetin alfa**)

RBC – red blood cell components of donor blood

EchoCG – echocardiography

EBMT – European Society for Blood and Marrow Transplantation

FISH – fluorescence in situ hybridization

Hb – hemoglobin

IBMTR – International Bone Marrow Transplant Registry

IPSS – International Prognostic Scoring System

IPSS-R – Revised International Prognostic Scoring System

MDS-CI – myelodysplastic syndrome-specific comorbidity index

NCCN – National Comprehensive Cancer Network

WPSS – WHO classification-based prognostic scoring system

** – 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

Anemic syndrome – anemic symptoms (fatigue, dizziness, exertional dyspnea, palpitations) can vary in severity and occur in 80–90% of MDS cases.

B-symptoms – weight loss, evening low-grade fever, night sweats

Hemorrhagic syndrome – clinically significant thrombocytopenia in blood counts is noted in 25–70% of cases, hemorrhagic manifestations at disease onset are noted in 15–30% (petechial skin and mucosal rashes, nasal, gingival, uterine, renal, and gastrointestinal bleeding, subconjunctival and cerebral hemorrhages) and reflect not only the degree of thrombocytopenia but also thrombopathies.

Dysplasia (from Greek δυσ dys – impairment and πλάθω plaseo – to form) refers to morphological deviations from normal development, identified at all levels from cells to tissues, organs, and individual body parts. Dysmyelopoiesis refers to any quantitative and qualitative abnormalities identified in hematopoietic cells and bone marrow hematopoietic tissue. When performing a differential myelogram count of myelokaryocytes, at least 500 nucleated bone marrow cells must be examined, and at least 200 leukocytes when counting peripheral blood leukocytes. Dysplasia is considered diagnostically significant when the proportion of cells with signs of dysplasia exceeds 10% of 100 counted erythrokaryocytes, 100 granulocytes, and at least 30 megakaryocytes.

Immunosuppressive therapy (IST) is a comprehensive set of therapeutic measures administered in stages over a year or more, including #cyclosporine** (CsA), antithymocyte globulin** (ATG), and other IST methods, making it possible to achieve the maximum positive effect and long-term survival in patients with MDS without and with hematopoietic hypoplasia.

Infectious complications: an increased frequency of infectious complications (10–40%) is caused by neutropenia and granulocyte dysfunction, which manifests as impaired phagocytic adhesion and chemotaxis. The most common infectious manifestations are bacterial pneumonias, skin abscesses, and opportunistic infections, including viral, Pneumocystis, and mycobacterial infections.

Bone marrow remission is a decrease in bone marrow blast cells to less than 5%, representing a reduction of more than 50% from baseline values, while peripheral blood hemogram parameters do not show complete recovery.

Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal hematopoietic disorders arising from clonal changes in the hematopoietic stem cell and characterized by cytopenia as a result of ineffective hematopoiesis, signs of dysmyelopoiesis, and a high risk of transformation into acute leukemia (AL).

MDS with single-lineage dysplasia – a variant of MDS characterized by single- or bilineage cytopenia, without an increased percentage of blast cells in the peripheral blood (<1%) and bone marrow (<5%), without an increase in ring sideroblasts and absolute monocytosis in the peripheral blood, while dysplasia in more than 10% of cells is detected in only 1 hematopoietic lineage. Anemia is most commonly the leading symptom in these patients.

MDS with ring sideroblasts (RS) and single-lineage dysplasia is a variant of MDS characterized by anemia, most commonly of normocytic or macrocytic character; diagnostically significant is the detection of ring sideroblasts in the bone marrow in 15% or more of erythroid lineage cells, regardless of the presence of an SF3B1 gene mutation, whereas in its presence, diagnostically significant is the detection of 5% or more ring sideroblasts; without an increased percentage of blast cells in the peripheral blood (<1%) and bone marrow (<5%), without absolute monocytosis in the peripheral blood, while dysplasia is detected in more than 10% of erythroid cells, and in less than 10% of granulocytic and megakaryocytic lineages.

MDS with RS and multilineage dysplasia is a variant of MDS characterized by cytopenia of any degree of severity; diagnostically significant is the detection of ring sideroblasts in the bone marrow in 15% or more of erythroid cells, regardless of the presence of an SF3B1 gene mutation, whereas in its presence, diagnostically significant is the detection of 5 or more ring sideroblasts; without an increased percentage of blast cells in the peripheral blood (<1%) and bone marrow (<5%), without absolute monocytosis in the peripheral blood, while dysplasia is detected in more than 10% of cells in the erythroid, granulocytic, and/or megakaryocytic lineages.

MDS with multilineage (multiple) dysplasia is a variant of MDS characterized by cytopenia of any degree of severity, without an increased percentage of blast cells in the peripheral blood (<1%) and bone marrow (<5%), without absolute monocytosis in the peripheral blood, while dysplasia is detected in more than 10% of cells in two or more hematopoietic lineages.

MDS with excess blasts-1 is a variant of MDS characterized by cytopenia of any degree of severity without absolute monocytosis, wherein blasts without Auer rods account for less than 5% in the peripheral blood, and from 5.0 to 9.9% in the bone marrow; the percentage of ring sideroblasts may be arbitrary, regardless of the SF3B1 gene mutation, as is the number of dysplastic cells.

MDS with excess blasts-2 is a variant of MDS characterized by cytopenia of any degree of severity without absolute monocytosis, wherein blasts, possibly with Auer rods, account for 5 to 19.9% in the peripheral blood, and 10 to 19.9% in the bone marrow; the percentage of ring sideroblasts may be arbitrary, as is the number of dysplastic cells. In cases where Auer rods are detected in blast cells in MDS with excess blasts-1, the diagnosis is verified as MDS with excess blasts-2.

MDS with isolated del(5q) (MDS-5q-) is a variant of MDS characterized by anemia, most commonly of macrocytic character, possibly combined with a normal or elevated platelet count, without an increased percentage of blast cells in the peripheral blood (<1%) and bone marrow (<5%), or absolute monocytosis in the peripheral blood, while dysplasia is detected in erythroid lineage cells and megakaryocytes; bone marrow cytogenetic testing reveals an isolated deletion of the long arm of chromosome 5 (del(5q)), or in combination with another abnormality, excluding chromosome 7 aberrations.

Unclassifiable MDS (MDS-U):

1. a variant of MDS meeting the criteria for MDS-SLD, MDS-RS-SLD, MDS-RS-MLD, MDS-MLD, and MDS-5q-, but with a peripheral blood blast cell count =1% on two or more measurements;

2. variants of MDS-SLD, MDS-RS-SLD, and MDS-5q- in which clinically significant pancytopenia is detected;

3. a variant of MDS in which clinically significant cytopenia with blastemia <2% and blast cells <5% in the bone marrow is detected, but dysplasia is found in less than 10% of cells in any hematopoietic lineage, alongside cytogenetic abnormalities pathognomonic for MDS.

Low-risk MDS: a group of patients categorized into very low, low, and intermediate risk groups (total score <3.5) according to the IPSS-R prognostic scoring system.

High-risk MDS: a group of patients categorized into intermediate (total score >3.5), high, and very high risk groups according to the IPSS-R prognostic scoring system.

MDS/MPN – myelodysplastic/myeloproliferative neoplasm – a group of clonal hematopoietic system disorders exhibiting features of both myelodysplastic syndrome (presence of dysplasia in more than 10% of cells of the granulocytic, and/or erythroid, and/or megakaryocytic lineages) and myeloproliferative neoplasm (leukocytosis, thrombocytosis), in the absence of evidence for BCR-ABL1-positive CML, polycythemia vera, primary myelofibrosis, essential thrombocythemia, in the absence of mutations in PDGFRα, PDGFRβ, FGFR1, PCM1-JAK2 genes, and in the absence of a history of cytotoxic therapy for another disease and the use of colony-stimulating factors. Splenomegaly or hepatosplenomegaly may occur in any MDS/MPN variant.

CMML – chronic myelomonocytic leukemia, an MDS/MPN variant characterized in the blood by a persistent monocyte count increase of 10% or more, with absolute values greater than 1×10⁹/L, the presence of dysplasia in more than 10% of cells in 1 or more hematopoietic lineages, a blast cell and equivalent count of less than 20%, and classic monocytes comprising 94% or more upon immunophenotyping. In the absence of dysplasia in more than 10% of cells: in the presence of cytogenetic and molecular genetic abnormalities characteristic of myeloid neoplasms; if monocytosis persists for 3 months or more in the absence of evidence for infectious and autoimmune processes.

CMML-0: a variant of CMML with a blast cell count in the blood analysis up to 1% or in the bone marrow up to 5%, with blast cells lacking Auer rods;

CMML-1: a variant of CMML with a blast cell count in the blood analysis from 2 to 4% or in the bone marrow from 5 to 9%, with blast cells lacking Auer rods;

CMML-2: a variant of CMML with a blast cell count in the blood analysis from 5 to 19% or in the bone marrow from 10 to 19% and/or Auer rods with any number of blast cells.

aCML — atypical chronic myeloid leukemia, bcr-abl1-negative — a variant of MDS/MPN characterized by an elevated peripheral blood leukocyte count of 13×10⁹/L or higher, an increased percentage of immature neutrophil forms (promyelocytes + myelocytes + metamyelocytes) of 10% or more, basophils <2%, monocytes <10%, with a blast cell count of less than 20%; in the bone marrow, the blast cell count is less than 20%, with proliferation of the granulocytic lineage and signs of dysmyelopoiesis in more than 10% of cells in 1 or more hematopoietic lineages.

MDS/MPN-RS-T — myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis, an MDS/MPN variant characterized by anemia, thrombocytosis of 450×10⁹/L or higher, and blastemia up to 1% in blood tests; detection of ring sideroblasts at 15% or higher in the bone marrow; blast cell count up to 5%; presence of dysplasia in 1 or more hematopoietic lineages and morphological features characteristic of myeloproliferative neoplasms; there must be no history of other myeloproliferative neoplasms or MDS (except MDS-RS); mutations in the SF3B1, JAK2, CALR, MPL genes may be present in the absence of chromosome 5 long arm deletion, and chromosome 3 long arm translocation and deletion.

MDS/MPN, unclassifiable — myelodysplastic/myeloproliferative neoplasm, unclassifiable, characterized by clinical and morphological features of both MDS and MPN that do not fulfill the criteria for any specific MDS, MPN, or MDS/MPN variant: blast cells less than 20% in the blood and bone marrow, presence of clinical and morphological features of myelodysplasia combined with clinical and morphological signs of a myeloproliferative process (leukocytosis >13×10⁹/L and thrombocytosis >450×10⁹/L).

Neutrophil response — an increase in the neutrophil count by more than 100% from baseline values.

Treatment failure — death or disease progression during therapy.

Overall survival (OS) — to assess OS, the time parameters of all patients included in the study are analyzed. The starting point is the date of therapy initiation or the date of diagnosis verification. Only death from any cause (early mortality, death during remission from any cause, death during relapse) is considered an event.

Acute leukemia (AL) — a heterogeneous group of clonal hematopoietic disorders resulting from a mutation in a hematopoietic stem cell (HSC) and leading to an increase in blast cells to more than 20% in the bone marrow and/or peripheral blood. Based on the lineage of the blast cells, AL is divided into:

Acute myeloid leukemia (AML) — myeloid lineage of blast cells.

Acute lymphoblastic leukemia (ALL) — lymphoid lineage of blast cells.

Complete remission (CR) — a state of the hematopoietic tissue in which hemoglobin is >110.0 g/L, neutrophils are ≥1.0×10⁹/L, blast cells are absent, platelets are >100.0×10⁹/L, and bone marrow blasts are <5%; persistent dysplasia may be present.

Polychemotherapy (PCT) — the most justified combination of antineoplastic (cytostatic) drugs that achieves the maximum positive effect, particularly CR, in hemoblastoses.

Disease progression — an increase in the blast cell count by more than 50% and transition from the initial MDS variant to a more advanced one (MDS-SLD to MDS-MD, MDS-MD to MDS-EB-1, MDS-EB-1 to MDS-EB-2) (characteristics of MDS variants are presented in section 1.5 "Classification of the disease or condition (group of diseases or conditions)", table 1), while blood counts may show a 50% decrease from peak values, a hemoglobin drop of more than 20 g/L, or the onset of transfusion dependence. In the presence of stable blast counts, worsening cytopenia without other causes is also a sign of disease progression.

Relapse after CR — an increase in blast cell count >5%; a decrease of 50% or more in platelet and neutrophil counts from peak values during remission; a hemoglobin drop of 15 g/L or more; and the onset of dependence on red blood cell transfusions.

Splenomegaly — in MDS, the spleen may be slightly enlarged by 1–2 cm; in MDS/MPN, spleen enlargement can be significant.

Stabilization — absence of partial remission, but no signs of progression for more than 8 weeks.

Transformation/progression — to AML is diagnosed when bone marrow aspirate or peripheral blood reveals more than 20% blast cells.

Bone marrow transplantation — this term encompasses hematopoietic stem cell transplantation of blood, bone marrow, and umbilical cord (placental) blood.

Platelet concentrate — a donor blood component containing platelets.

Platelet response — an increase in the platelet count >30×10⁹/L and a reduction in dependence on platelet transfusions.

Cytogenetic remission — complete clinical and hematological remission in which initial karyotype abnormalities are no longer detected by cytogenetic methods; the karyotype must be normal. A reduction of at least 50% in the number of cells with chromosomal aberrations is evaluated as a partial cytogenetic response.

Partial remission (PR) — the same criteria as for CR, except that bone marrow blasts constitute more than 5%.

Erythroid response — an increase in hemoglobin level by 15 g/L or more and a reduction in dependence on donor red blood cell transfusions.

Red blood cell components of donor blood (RBCCD) — donor blood components containing red blood cells (packed red blood cells, red blood cell suspension, etc.).

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Myelodysplastic syndromes represent a heterogeneous group of clonal hematopoietic disorders characterized by cytopenia, signs of dysmyelopoiesis, and a high risk of transformation into AML [1, 2].

Myelodysplastic/myeloproliferative neoplasm is a heterogeneous group of hematologic disorders characterized by the simultaneous presence of features of both myelodysplastic syndrome and myeloproliferative neoplasm [120].

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

In 80–90% of cases, the etiology of MDS and MDS/MPN is unknown; in 10–15% of cases, the disease was preceded by cytostatic and/or radiation therapy administered for a systemic connective tissue disease or another hemato-oncological or oncological process. Factors that increase the risk of developing MDS and MDS/MPN include smoking, exposure to gasoline, insecticides, pesticides, and organic substances.

The study of the pathogenesis of MDS and MDS/MPN over several decades has identified several fundamental stages in the development of these disorders. Exposure of pluripotent hematopoietic stem cells (HSCs) to damaging factors leads to the establishment of clonal hematopoiesis involving all cell lineages, reactive alterations in the stromal microenvironment and the lymphatic system, and increased proliferative activity coupled with bone marrow (BM) cell death. The emergence of new mutations drives the further clonal evolution of the existing pathological clone, accompanied by a decrease in programmed cell death (apoptosis) and transformation into AL [1, 2, 120].

1.3 Epidemiology of the Disease or Condition

In Europe and the USA, the incidence of MDS in the general population is approximately 4–5 cases per 100,000 population per year. More than 80% of MDS patients are over 60 years of age. After age 60, the incidence increases to 20–50 cases per 100,000 population per year. Overall, approximately 25,000 new cases are diagnosed annually in Europe. Given the steady "aging" of the European population, the number of MDS patients is expected to increase in the coming decades [1–6].

There are no official statistical data on the incidence and prevalence of MDS in Russia.

The incidence of CMML is 0.4 per 100,000 population, increasing to 3.8 per 100,000 among individuals over 80 years of age. Men are affected more frequently (0.5 per 100,000 males) than women (0.2 per 100,000 females). The median age is 65–75 years. The incidence of aCML is 1–2 cases per 100 cases of BCR-ABL-positive CML. The median age is 70–80 years, and the male-to-female ratio is 1:1. The median age for MDS/MPN-RS-T is 74 years [120].

1.4 Features of Coding the Disease or Condition

Myelodysplastic syndromes (D46)

D46.0 Refractory anemia without sideroblasts, so specified

D46.1 Refractory anemia with sideroblasts

D46.2 Refractory anemia with excess blasts

D46.4 Refractory anemia, unspecified

D46.5 Refractory anemia with multilineage dysplasia

D46.6 Myelodysplastic syndrome with isolated del(5q) chromosomal abnormality

D46.7 Other myelodysplastic syndromes

D46.9 Myelodysplastic syndrome, unspecified

Myelodysplastic/myeloproliferative neoplasms

C93.1 Chronic myelomonocytic leukemia

C92.2 Atypical chronic myeloid leukemia, BCR-ABL-negative.

C94.6 Myelodysplastic and myeloproliferative disease, not elsewhere classified

1.5 Classification of the disease or condition

Since 2000, MDS diagnoses have been verified using the World Health Organization (WHO) classifications (2008 revision [7]), which underwent significant updates in the 2017 revision:

1. Changes in MDS nomenclature. The current classification removes the key term "refractory anemia" for all MDS variants. The term "myelodysplastic syndrome" has become central for modern designation of MDS variants. For example, MDS with ring sideroblasts (RS) and multilineage dysplasia, MDS with excess blasts-2;

2. Specifics of counting blast cells in the bone marrow (BM) as a percentage of all nucleated bone marrow cells;

3. Interpretation of an increased number of ring sideroblasts depending on the presence or absence of a mutation in the SF3B1 gene: if the SF3B1 mutation is present, the threshold for ring sideroblasts is ≥5%, if absent or indeterminate, ≥15%;

4. In MDS patients with a deletion of the long arm of chromosome 5, one additional karyotype abnormality is permitted, excluding aberrations of chromosome 7.

In view of the above, MDS variants according to the current 2017 WHO criteria are presented below [8].

1. MDS with single lineage dysplasia (MDS-SLD):

2. MDS with multilineage dysplasia (MDS-MLD).

3. MDS with ring sideroblasts (MDS-RS):

– MDS with ring sideroblasts and single lineage dysplasia (MDS-RS-SLD).

– MDS with ring sideroblasts and multilineage dysplasia (MDS-RS-MLD).

4. MDS with isolated deletion of the long arm of chromosome 5 (MDS-5q–).

5. MDS with excess blasts:

– MDS with excess blasts-1 (MDS-EB-1);

– MDS with excess blasts-2 (MDS-EB-2);

6. MDS, unclassifiable (MDS-U).

Criteria for MDS variants are presented in Table 1.

Table 1. WHO 4th edition revised classification of MDS (2017) [8]

Pathological and anatomical examination of bone marrow biopsy (surgical) material (trephine biopsies) in patients with MDS most often reveals normo- or hypercellular BM, and only in 10–15% of cases is hematopoietic tissue hypoplasia detected, and in 10–15% — grade 2–3 stromal fibrosis, which makes it possible to distinguish MDS with hematopoietic hypoplasia or MDS with stromal fibrosis. It is advisable to reflect these features of the MDS course in the clinical diagnosis, for example: MDS with excess blasts-1, occurring with grade 2 stromal fibrosis; or MDS with multilineage dysplasia, occurring with hematopoietic hypoplasia.

This specification makes it possible to assume the features of the disease course, determine the treatment tactics and its effectiveness, as well as the probability of progression to AML.

MDS/MPN variants according to the current 2017 WHO criteria are presented below [120].

Table 2. Classification of MDS/MPN according to the 4th edition of the WHO from 2017 [120]

Based on the leukocyte count, chronic myelomonocytic leukemia is divided into 2 subtypes: with leukocytes <13x10⁹/L — myelodysplastic CMML (MD-CMML),

with leukocytes >13x10⁹/L — myeloproliferative CMML (MP-CMML).

Based on the blast cell count, CMML is divided into 3 variants: CMML-0 — with a blast cell count in the bone marrow <5%, and in the blood up to 1%; CMML-1 with a blast cell count in the bone marrow of 5–9%, and in the blood of 2–4%; CMML-2 — with a blast cell count in the bone marrow of 10–19% and in the blood of 5–19%.

In CMML, bone marrow stromal fibrosis can be detected in 30% of cases upon pathomorphological examination [120].

Myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms that developed after prior cytotoxic (drug or radiation) exposure, previously called "secondary", are classified in the 2017 WHO classification into the group of therapy-related myeloid neoplasms (t-MDS, t-MDS/MPN) [120].

In 2022, the 5th WHO revision of the classification of MDS and MDS/MPN, as well as the classification criteria of the International Consensus Classification (ICC), were presented for discussion, which have significant discrepancies on some issues; in this regard, a group of Russian experts considers it possible to continue classifying MDS and MDS/MPN variants in accordance with the 4th edition of the 2017 WHO classification.

1.6 Clinical presentation of the disease or condition

The main clinical manifestations of MDS are non-specific and are most often caused by both quantitative and qualitative changes in the hematopoietic system: cytopenic syndrome (anemia syndrome, hemorrhagic syndrome, leukopenia), infectious complications, B-symptoms, mild splenomegaly, autoimmune manifestations.

Autoimmune manifestations: in ~10% of cases, MDS manifests with an autoimmune process: systemic vasculitis, necrotizing panniculitis, seronegative arthritis, polymyalgia rheumatica, Coombs-positive hemolytic anemia, pericarditis, pleuritis [1–5].

2. Diagnostics, medical indications and contraindications for diagnostic methods

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

To verify the diagnosis of MDS, a set of necessary and decisive criteria should be taken into account.

1. Necessary criteria

• Stable cytopenia in 1 or more lineages for ≥4 months, in particular:

  hemoglobin levels <110 g/L, neutrophil count <1.8×10⁹/L, platelet count <100×10⁹/L.

• Absence of other hematological and non-hematological diseases presenting with cytopenias.

2. Decisive criteria (at least 1 criterion)

• Dysplasia in ≥10% of all cells of the erythroid and/or granulocytic, and/or megakaryocytic lineages, revealed by morphological examination of the bone marrow.

• ≥15% RS or ≥5% RS combined with an SF3B1 mutation.

• 5–19% blast cells in the BM or 2–19% blast cells in the peripheral blood.

• Typical karyotype abnormalities (–7, 5q–, etc.) detected by standard cytogenetic testing or FISH.

3. Additional criteria

If the necessary criteria (1) are met, but the decisive criteria (2) are not, and there is a clinical picture caused by macrocytic anemia and transfusion dependency, confirmation of the diagnosis may include:

● An atypical immunophenotype of BM cells with multiple MDS-associated aberrations detected by immunophenotyping and confirming a monoclonal population of erythroid and myeloid cells.

● Changes in the histological picture of the BM, including immunohistochemical examination, confirming MDS [9].

The diagnosis of MDS is also confirmed with lesser cytopenia (e.g., hemoglobin 115 g/L, platelet count >100×10⁹/L) if BM cytogenetic testing reveals karyotype changes characteristic of MDS.

Signs of myelodysplasia can be detected in the BM or peripheral blood not only in MDS, but also in other non-clonal diseases.

1. Dyserythropoiesis can be observed in:

• In _B12/folate-deficient anemias;

• congenital dyserythropoietic anemia;

• autoimmune hemolytic anemias;

• paroxysmal nocturnal hemoglobinuria (PNH);

• alcohol intoxication;

• viral infections (hepatitis B and C, human immunodeficiency virus (HIV), Epstein–Barr virus (EBV), parvovirus B19);

• infectious diseases (miliary tuberculosis, malaria, leishmaniasis);

• poisoning with gasoline, lead, and other heavy metals;

• as a manifestation of a paraneoplastic reaction, including bone marrow involvement in lymphomas/leukemias;

• autoimmune diseases (systemic lupus erythematosus, autoimmune thyroiditis);

• copper deficiency and/or excessive dietary zinc intake [10,11].

2. Dysgranulopoiesis may be observed:

• with the use of medications (colony-stimulating factors [recombinant human granulocyte colony-stimulating factor (rhG-CSF)], antimetabolites);

• in viral infections (HIV, EBV);

• as a manifestation of a paraneoplastic reaction;

• after chemotherapy (CT) and during the bone marrow recovery period.

3. Dysmegakaryocytopoiesis may be observed:

• in HIV infection;

• reactive/paraneoplastic myelofibrosis;

• after hematopoietic stem cell transplantation (HSCT) and prior chemotherapy.

When performing differential diagnosis of MDS, it is extremely important to take into account anamnestic data regarding existing chronic diseases that may present with cytopenic syndrome, previous chemo- or radiotherapy, immunotherapy, radioiodine therapy, occupational hazards associated with exposure to harmful substances (especially benzene), alcohol consumption, smoking, and a predisposition to spontaneous bleeding and infections. In young patients, it is necessary to consider conditions indicating hereditary hematopoiesis disorders, such as Fanconi anemia and telomere length-related disorders (hereditary dyskeratosis, etc.). For elderly patients, secondary causes of changes must be ruled out, primarily those associated with solid tumors. In the absence of an increased blast cell count and/or characteristic karyotypic abnormalities, the diagnosis of MDS is a diagnosis of exclusion that requires a thorough workup and serial bone marrow examinations.

To verify a diagnosis of MDS/MPN, the presence of myelodysplastic and myeloproliferative features is required. Signs of myelodysplasia are described above.

2.1 Complaints and Anamnesis

• In all patients with suspected MDS, in order to clarify the diagnosis and identify clinically significant comorbid conditions during the collection of complaints and medical history, it is recommended to pay attention to the time of onset of the first symptoms, the dynamics of disease progression, the presence of comorbidities, occupational hazards and living conditions of the patient, and previous therapy for other diseases (especially oncohematological, autoimmune, etc.) [1–5].

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

Comments: there are no specific symptoms in MDS. The most common reasons for seeking medical attention are anemia-related complaints (weakness, fatigue, decreased exercise tolerance), less commonly hemorrhagic syndrome and infectious complications; the duration of history ranges from 1 month to several years.

2.2 Physical Examination

• All patients with suspected or confirmed MDS, as well as patients with MDS/MPN, are recommended to undergo a physical examination at the time of diagnosis verification and during follow-up [1–4, 120].

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

Comments: during the physical examination, it is necessary to assess: the condition of the skin and mucous membranes; the presence or absence of signs of hemorrhagic and edematous syndromes; specific skin lesions, hepatosplenomegaly, lymphadenopathy; signs of dysfunction of the central nervous, cardiovascular, pulmonary, urinary, endocrine, and musculoskeletal systems, and the gastrointestinal tract. To calculate body surface area, height and weight measurements are required, including prior to each treatment cycle.

2.3 Laboratory Diagnostics

The leading symptoms of MDS are cytopenias, which are diagnosed when hematological parameters persistently drop below threshold values: Hb <110 g/L and/or absolute neutrophil count (ANC) <1.8×10⁹/L, and/or platelets <100×10⁹/L. In MDS/MPN, blood test changes may present similarly to MDS in combination with leukocytosis >13×10⁹/L, thrombocytosis >450×10⁹/L, while in CMML, a mandatory condition is the presence of monocytosis >10% and absolute values >1.0×10⁹/L.

All diagnostic procedures are aimed at ruling out reactive cytopenias, cytoses, or other clonal disorders of the hematopoietic system.

The range of laboratory tests that will assist in verifying the diagnosis of MDS and MDS/MPN is presented below.

Following a comprehensive medical evaluation of the patient that rules out a "secondary" nature of cytopenia, cytosis, and monocytosis, a hematological workup is required, which includes:

• obtaining a bone marrow cytologic preparation by aspiration;

• cytological examination of a bone marrow smear (myelogram) to detect qualitative and quantitative changes in the cellular composition of the bone marrow;

• cytochemical examination of the bone marrow micropreparation when the blast cell count exceeds 5% to detect Auer rods;

• determination of sideroblasts and siderocytes in the bone marrow;

• cytogenetic examination (karyotype) of the bone marrow (study of bone marrow cells using differential chromosome banding to detect clonal tumor cells);

• immunophenotyping of hematopoietic progenitor cells in the bone marrow to detect signs of dysmyelopoiesis and determine the blast cell variant;

• molecular genetic testing for gene mutations;

• obtaining a bone marrow histological preparation (trephine biopsy) followed by pathomorphological examination of the bone marrow biopsy (surgical) material.

Initial confirmation of MDS should preferably be performed in specialized hematological centers, departments, or offices. For adequate verification of the diagnosis and assessment of disease dynamics, repeat bone marrow examinations are required after several weeks, months, or even years.

A diagnosis of MDS is considered valid if, after 4 months of observation, no other hematological or non-hematological disease has been diagnosed that could explain the presence of cytopenia. This time interval is most justified for patients without an excess of blasts presenting with cytopenias that do not require blood component replacement therapy. If an increased blast count and/or cytogenetic aberrations and clinically significant cytopenia are detected, a diagnosis of MDS and MDS/MPN can be established immediately based on the complete hematological workup data, without a period of dynamic observation. To verify the diagnosis, determine the disease variant, and select treatment tactics, a complete medical and hematological evaluation must be performed [1–5].

• In all patients with suspected MDS and MDS/MPN, as well as after disease verification throughout the entire period of observation and treatment, it is recommended to perform a complete blood count (CBC) with differential leukocyte count (leukocyte formula). Evaluation of blood reticulocyte count. Evaluation of blood platelet count using an automated analyzer to clarify the MDS variant, risk group category (see section 7.1 of these guidelines), and treatment strategy [12].

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

Comments: the detected changes (hemoglobin <110 g/L and/or absolute neutrophil count <1.8×10⁹/L and/or platelets <100×10⁹/L in the presence of signs of dysmyelopoiesis and other MDS criteria) will allow verification of the diagnosis of MDS or MDS/MPN, determination of the risk group, and assist in choosing treatment tactics. The frequency of testing depends on the MDS or MDS/MPN variant, clinical manifestations, and ongoing therapy, and can range from daily testing to quarterly testing. When frequent assessments are needed, especially during therapy, a complete blood count (CBC) may be performed on an automated analyzer without manual differential leukocyte counting.

If giant platelets are reported by an automated analyzer, it is advisable to recount platelets and analyze cytomorphological features during blood examination, especially at the time of verifying the diagnosis of MDS and MDS/MPN, since the presence of giant platelet forms may lead to an underestimation of the platelet count when measured by an automated analyzer.

• All patients with suspected MDS and MDS/MPN, as well as after disease verification throughout the entire period of follow-up and treatment, are recommended to undergo a general (clinical) urinalysis to diagnose comorbid conditions and signs of nephrotoxicity associated with the ongoing therapy [1, 2].

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

Comments: the frequency of the test depends on the MDS or MDS/MPN variant, clinical manifestations, and ongoing therapy, and can range from daily to annual.

• All patients with suspected MDS and MDS/MPN, after disease verification throughout the entire period of follow-up and treatment, are recommended to undergo blood tests: total blood protein, blood albumin, blood immunoglobulins, blood albumin/globulin ratio, blood urea, blood creatinine, total blood bilirubin, free and conjugated blood bilirubin, blood alanine aminotransferase activity, blood aspartate aminotransferase activity, blood lactate dehydrogenase activity, blood alkaline phosphatase activity, blood cholesterol, and blood glucose to detect comorbid conditions and determine the MDS management strategy [1, 2, 4, 5].

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

Comments: verification of deviations from normal values will help determine the tumor burden, presence of hemolysis signs and comorbid conditions, as well as assess the development of adverse events during the ongoing therapy. The frequency of testing and biochemical parameters depend on the MDS and MDS/MPN variant, clinical manifestations, and ongoing therapy, and can range from daily to quarterly. Frequent testing may be limited to monitoring clinically significant parameters only.

• All patients with suspected MDS and MDS/MPN, as well as after disease verification, throughout the entire period of follow-up and treatment, are recommended: Serum iron test. Total iron-binding capacity test. Serum ferritin test. Serum transferrin test. Transferrin saturation test, with a frequency of once every 3–6 months to assess the presence or absence of iron deficiency, as well as to determine the baseline serum ferritin level and its changes during therapy, for timely prescription of iron chelation therapy and evaluation of its efficacy [1, 2, 4, 5].

Comments: if serum ferritin is elevated, it is advisable to test the serum C-reactive protein (CRP) level to rule out an inflammatory nature of the changes.

• All patients with suspected MDS and MDS/MPN, after diagnosis verification throughout the entire period of follow-up and treatment, are recommended to determine blood vitamin B12 (cyanocobalamin) and serum folic acid levels to assess potential B-vitamin deficiency and prescribe appropriate therapy in case of their deficiency [1, 2, 4, 5].

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

Comments: during MDS and MDS/MPN therapy, it is advisable to determine blood vitamin B12 and serum folic acid levels 1 to 4 times a year.

• All patients upon verification of low-risk MDS and MDS/MPN (see section 7.1 of these guidelines) with clinically significant anemia are recommended, prior to initiating transfusion therapy with red blood cell components, to test blood erythropoietin (EPO) levels to determine the management strategy, in particular, the possibility of prescribing hemopoietic stimulants (other antianemic drugs - erythropoiesis-stimulating agents (ESAs)) [13].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

• All patients for the verification of MDS and MDS/MPN, and throughout follow-up upon the appearance of a clinical and laboratory presentation of hemolytic anemia, are recommended to undergo direct and indirect antiglobulin tests (direct Coombs test and indirect Coombs test) and a blood haptoglobin test [14].

GCR BLEL 3Grade of Recommendation B (Level of Evidence – 3)

Comments: upon the appearance of a clinical and laboratory presentation of hemolytic anemia, the autoimmune nature of the changes must be ruled out.

• Patients with a bone marrow blast cell count of less than 5%, as well as with clinical and laboratory signs of intravascular hemolysis upon verification of MDS and MDS/MPN, and upon their appearance during follow-up and treatment, are recommended to undergo peripheral blood cell immunophenotyping for the diagnosis of paroxysmal nocturnal hemoglobinuria using an expanded panel of markers, including FLAER (fluorescent-labeled aerolysin) to detect a paroxysmal nocturnal hemoglobinuria (PNH) cell clone [15].

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

Comments: the presence of a PNH clone in MDS patients is detected in 18–25% of cases, and the clone size can vary from minor to clinically significant. If thrombotic complications are detected, patients with a PNH clone may require appropriate therapy.

• All patients upon verification of MDS and MDS/MPN and throughout follow-up and treatment are recommended to undergo testing: Coagulogram (exploratory hemostasis assessment). Activated partial thromboplastin time. Determination of prothrombin (thromboplastin) time in blood or plasma. Blood fibrinogen level. Platelet aggregation test (if indicated) during specific therapy, prior to invasive procedures (obtaining bone marrow cytologic preparation via puncture, obtaining bone marrow histologic preparation (trephine biopsy), catheterization of the subclavian and other central veins, surgical treatment) to assess the blood coagulation system and liver protein-synthetic function [1, 2, 4, 5].

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

Comments: if abnormalities in the blood coagulation system are detected, they are corrected.

• All patients with suspected MDS and MDS/MPN, as well as a confirmed diagnosis of MDS and MDS/MPN who develop severe infectious complications during specific therapy, are recommended to undergo blood immunoglobulin levels, blood immunoglobulin A level, blood immunoglobulin G level, blood immunoglobulin M level, blood immunoglobulin monoclonality testing by immunofixation, serum C-reactive protein level, and urine paraprotein testing [16–18].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: the detected changes will make it possible to rule out the secretion of a pathological protein and determine the supportive care strategy at various stages of specific MDS therapy.

• All patients with suspected MDS and MDS/MPN, as well as upon the appearance of symptoms characteristic of autoimmune connective tissue diseases, are recommended: Antistreptolysin-O in blood serum. Rheumatoid factor in blood. Anti-native DNA antibodies to diagnose autoimmune diseases [19].

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

Comments: autoimmune connective tissue diseases often present with cytopenic syndrome, which requires differential diagnosis between MDS and MDS/MPN; at the same time, symptoms and markers of autoimmune connective tissue diseases are detected in 10% of MDS cases and in CMML.

• All patients with suspected MDS and MDS/MPN and during subsequent treatment at least once a year are recommended determination of class M and G antibodies (IgM, IgG) to human immunodeficiency virus HIV 1/2 in blood; molecular biological blood testing for hepatitis B virus and hepatitis C virus; antibodies to Treponema pallidum in blood; to rule out comorbid conditions [1, 2, 4, 5].

  Level of recommendation C (evidence level – 5)

Comments: to rule out cytopenia associated with HIV infection, if positive markers are detected – initiate antiviral and antibacterial therapy. If acute or chronic viral hepatitis is suspected, molecular biological blood testing for hepatitis B virus and molecular biological blood testing for hepatitis C virus is performed. If positive markers are detected – initiate antiviral therapy.

• For patients with prolonged cytopenia in the presence of episodes of low-grade or febrile fever to verify the diagnosis of MDS or MDS/MPN, as well as during MDS therapy to rule out comorbid conditions, it is recommended to perform molecular biological blood testing for Herpes simplex virus; determination of antibodies to Herpes simplex virus in the blood; molecular biological blood testing for Cytomegalovirus; determination of class M and G antibodies (IgM, IgG) to Epstein–Barr virus in the blood [1].

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

Comments: if positive markers are detected and a characteristic clinical picture is present, antiviral therapy should be initiated.

• For all patients with Hb < 100 g/L and erythroid lineage of less than 10%, it is recommended to perform molecular biological testing of peripheral and umbilical cord blood for Parvovirus B19, molecular biological testing of chorionic villi, placental biopsy specimens, bone marrow aspirates for Parvovirus B19 to determine the presence of Parvovirus B19 infection [20], as well as the determination of class G (IgG) and class M (IgM) antibodies to Parvovirus B19 in the blood.

GCR CLE 5Level of recommendation C (level of evidence – 5)

Comments: if positive markers are detected, initiate specific therapy.

• For patients with isolated anemia, especially at a young age, in the presence of signs of hemolysis for the verification of the diagnosis of MDS, as well as upon the appearance of signs of hemolysis during therapy, it is recommended to identify hemoglobin types and perform a quantitative assessment of the ratio of hemoglobin types [21].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: this type of study can only be performed in research centers.

• For patients in whom cytochemical examination of erythrokaryocytes reveals ring sideroblasts in more than 15% of cells, to exclude trace element deficiency or excess for differential diagnosis, it is recommended to test blood copper and zinc levels [22, 23].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: if changes are detected, implement their correction.

• For all patients with cytopenic syndrome, as well as during long-term follow-up, it is recommended to test the blood thyroid-stimulating hormone (TSH) level to rule out hypothyroidism as part of the differential diagnosis and autoimmune thyroiditis [5, 24].

GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)

Comments: if changes are detected, an initial appointment (examination, consultation) with an endocrinologist and administration of therapy are indicated.

• For all patients to verify the diagnosis, determine the risk group according to prognostic scoring systems, detect disease progression to MDS with excess blasts, MDS/MPN, or acute leukemia, and confirm the achievement of remission or resistance to ongoing therapy, it is recommended to obtain a bone marrow cytologic preparation by sternal puncture or iliac crest puncture followed by cytologic examination of the bone marrow smear (myelogram). If a "dry tap" is obtained, perform a cytologic examination of bone marrow trephine biopsy imprints [25–28].

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

Comments: counting the presence and severity of dysplasia in percentage terms is necessary for diagnosis verification and when disease progression is suspected.

• For patients in whom bone marrow examination reveals dysplasia in only one hematopoietic lineage in less than 10% of cells, with no increase in blast count in peripheral blood or bone marrow, ring sideroblasts accounting for less than 15% of erythroid precursors, and no cytogenetic abnormalities detected, it is recommended to repeat the collection of a bone marrow cytologic preparation by puncture followed by cytologic examination of the bone marrow smear (myelogram) in 1–6 months, depending on the dynamics of the clinical manifestations of the disease, for definitive verification of the diagnosis, including MDS [25–27].

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

Comments: such patients typically have moderate cytopenia, and rapid disease progression is unlikely in them.

• For all patients to verify the diagnosis of MDS and MDS/MPN, detect disease progression, and in some cases evaluate therapy efficacy, it is recommended to examine the bone marrow for siderocytes and sideroblasts to identify and count ring sideroblasts relative to the total number of erythrokaryocytes, when the blast cell count is less than 5% and the erythroid lineage is 10% or more [27–29].

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

Comments: the Prussian blue reaction is used for this purpose. Based on the results obtained, the variant of MDS or MDS/MPN is determined, and treatment tactics are chosen.

• For all patients with a blast cell count from 5.0% to 9.9% to verify the MDS or CMML variant, it is recommended to perform cytochemical examination of the bone marrow micropreparation to detect Auer rods in blast cells [27–29].

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

Comments: For a more accurate determination of the MDS and MDS/MPN variant, it is advisable to perform a myeloperoxidase cytochemical reaction for better visualization of Auer rods.

• For all patients, it is recommended to perform cytogenetic examination (karyotype) of bone marrow cells to verify the diagnosis of MDS or MDS/MPN, determine the risk group according to prognostic scoring system criteria, detect clonal evolution, and confirm the achievement of cytogenetic remission [9, 30–38].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: in accordance with the detected karyotype changes, the MDS variant will be determined and the issue of treatment tactics will be resolved.

• For all patients with a normal karyotype, repeated absence of mitoses during cytogenetic examination (karyotype) at the time of diagnosis verification, or with a low mitotic index or a small number of abnormal mitoses preventing the diagnosis of karyotype abnormalities, to verify the diagnosis of MDS or MDS/MPN and determine the prognostic risk group, as well as to evaluate the efficacy of MDS therapy, if available, it is recommended to perform molecular cytogenetic testing (FISH method) for one pair of chromosomes to detect abnormalities of chromosomes 5, 7, 8 (only in the absence of mitoses), 3, 17, and others [39].

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

Comments: detection of hidden karyotype abnormalities helps verify the disease variant and determines the choice of treatment tactics. Today, this type of testing is only available in research centers or specialized laboratories.

• For all patients, it is recommended to obtain a bone marrow histologic preparation (trephine biopsy) and perform pathomorphological examination of the bone marrow biopsy (surgical) material to verify the diagnosis of MDS or MDS/MPN and for dynamic monitoring; in complex cases of diagnosing MDS without excess blasts for diagnosis verification and with unexplained worsening of cytopenic syndrome, performing this study bilaterally is possible [9, 40–44].

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

Comments: pathomorphological examination of the bone marrow allows for the verification of the diagnosis of MDS or MDS/MPN, identification of histological features of the disease, and a differentiated approach to therapy selection.

• For all patients at the time of verification of MDS or MDS/MPN, as well as during treatment and disease progression, in cases requiring more precise verification of bone marrow changes (presence of dysplastic megakaryocytes, atypically located immature precursors and cells with blast morphology, in the presence of stromal fibrosis and lymphoid aggregates), it is recommended to perform pathomorphological examination of bone marrow biopsy (surgical) material using immunohistochemical (IHC) methods [9, 45–47].

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

Comments: pathomorphological examination of bone marrow biopsy (surgical) material using immunohistochemical methods — IHC studies in MDS or MDS/MPN are performed on sections of paraffin blocks from bone marrow trephine biopsies. CD34 antibodies are used for the visualization and semiquantitative assessment of cells with blast morphology outside endosteal niches; CD61/CD42b antibodies are used to identify the megakaryocytic lineage, detect megakaryoblasts, small megakaryocytes with mono-bilobular nuclei, and microforms (note — hypolobular nuclei do not have independent diagnostic value as a sign of megakaryocytic lineage dysplasia; it is better to use this term less frequently, as such cells are often found among megakaryocytes in the older age group and in autoimmune diseases). Immunohistochemical studies can also reveal: a decrease in the expression of TdT+, CD19+, and PAX5+, which is characteristic of MDS; in differential diagnosis — signs of monocytic differentiation with a "left shift" of the granulocytic lineage associated with chronic myelomonocytic leukemia, a disease from the MDS group.

The recommended panel of antibodies for pathomorphological examination of bone marrow biopsy (surgical) material using immunohistochemical research methods during the differential diagnosis of MDS is as follows:

– granulocytic lineage – myeloperoxidase (MDS is characterized by a decrease in the intensity of myeloperoxidase expression and the number of positive cells);

– monocytic lineage – CD14, CD68 (PG-M1), CD163, lysozyme;

– erythroid lineage – hemoglobin, CD71, glycophorin A or C;

– megakaryocytic lineage – CD61, CD42b,

– immature cells with blastic morphology – CD34 and/or CD117/CD34 (in combination with CD71 for visualization of immature erythroid precursors), etc.

– Gomori stain – to detect bone marrow stromal fibrosis.

• In diagnostically complex cases in patients with suspected MDS, MDS/MPN, and upon disease progression, if laboratory facilities permit, it is recommended to perform immunophenotyping of bone marrow hematopoietic progenitor cells to detect markers of hematologic malignancies and identify immunological signs of dysplasia, as well as to determine minimal residual disease markers in hematologic malignancies following specific therapy [48–53].

GCR BLEL 3Grade of Recommendation B (Level of Evidence – 3)

Comments: immunophenotyping of bone marrow hematopoietic progenitor cells makes it possible to identify specific cellular changes in individual bone marrow hematopoiesis lineages. No single isolated immunophenotypic parameter has proven diagnostic significance for MDS, but analyzing combinations of individual features helps distinguish this disease from other types of cytopenia. However, this diagnostic method is available only in federal centers or within clinical trials.

• All patients with blood monocytosis greater than 1x10⁹/L are recommended to undergo immunophenotyping of biological material to detect markers of hematologic malignancies and determine the proportion of classical monocytes in the blood [121, 122]

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: immunophenotyping of biological material to detect markers of hematologic malignancies makes it possible to determine the number of classical monocytes (CD14+, CD16-) among the fraction of mature blood monocytes, which in most cases of CMML account for >94%.

• All patients with a confirmed diagnosis of MDS or MDS/MPN, if laboratory facilities permit, are recommended molecular genetic testing for mutations in the SF3B1 gene in the blood, molecular genetic testing for mutations in the TP53 gene in the blood, molecular genetic testing for mutations in the FLT3 gene (with 10% or more blast cells), molecular genetic testing for mutations in the KRAS gene in biopsy (surgical) material, molecular genetic testing for mutations in the NRAS gene in biopsy (surgical) material, molecular genetic testing for mutations in the CEBPA gene in the blood, molecular genetic testing for mutations in the IDH1 gene in biopsy (surgical) material, molecular genetic testing for mutations in the IDH2 gene in biopsy (surgical) material, molecular genetic testing for NPM1 (nucleophosmin 1) gene mutations in the bone marrow or molecular genetic testing for NPM1 gene mutations by sequencing, as well as molecular genetic testing for mutations in other genes (ASXL1, ETV6, RUNX1, GATA2, DNMT3A, TET2, SRSF2, EZH2, U2AF1, CBL, MLL SEPBP1, UBA1) in the blood or BM to determine the disease prognosis [5, 54–56, 155].

  Level of recommendation evidence C (reliability level of evidence – 4)

Comments: this diagnostic method is available only in federal centers or within clinical trials. Having information on mutational status allows for a more accurate prognosis of MDS and MDS/MPN.

• Patients with MDS presenting with stromal fibrosis or thrombocytosis, as well as all patients with suspected MDS/MPN, are recommended molecular genetic testing for Ph-negative myeloproliferative neoplasm markers (mutations in Jak2, MPL, and CALR genes) to determine the disease variant, prognosis, and treatment strategy [57, 58].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

• All patients with suspected MDS/MPN are recommended to undergo quantitative BCR-ABLp210 mRNA expression testing, molecular genetic testing for PDGFRA gene mutations, as well as molecular genetic testing for mutations in the PDGFRB, FGFR1, PCM-JAK2 genes to rule out other myeloproliferative neoplasms [120].

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

• All patients under 40 years of age with suspected constitutional hematopoiesis aplasia preceding the development of MDS are recommended to undergo cytogenetic testing (karyotype) of the blood and a DEB test (diepoxybutane test) to rule out Fanconi anemia [59].

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

• Patients with intermediate-, high-, and very high-risk MDS according to IPSS-R, MDS/MPN: CMML-2 (high-risk group), aCML (see section 7.1 of these guidelines), who may be considered candidates for hematopoietic stem cell transplantation (HSCT) from a related or unrelated donor, are recommended to undergo high-resolution HLA molecular genetic histocompatibility testing using sequencing for bone marrow donor selection [1, 4, 5, 60].

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

Comments: HLA class I and II antigen typing of patients with MDS and MDS/MPN and potential related donors is performed to identify tissue-compatible identical pairs for HSCT.. Typing of recipients who do not have potential related donors is also advisable to search for an unrelated donor in Russian and international registries.

• All patients with MDS and MDS/MPN scheduled for blood component replacement therapy are recommended to undergo ABO blood group typing, Rhesus factor (Rh0[D] antigen) determination, C, c, E, e, Cw, K, k antigen phenotyping, and anti-erythrocyte antibody screening to select transfusion media and minimize transfusion reactions [61].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

Comments: given the high frequency of blood transfusions and the subsequent development of sensitization to donor blood components and erythrocyte chimerism, transfusions should be performed taking the phenotype into account.

• All patients undergoing therapy with #cyclosporine** are recommended to have blood cyclosporine A levels tested to select the optimal drug dose [1].

GCR CLOCE 4Grade of Recommendation C (Level of Evidence 4)

Comments: considering individual characteristics, the selection of the optimal cyclosporine dose is carried out taking into account blood biochemical parameters (blood urea, blood creatinine, total bilirubin, free and conjugated bilirubin) and cyclosporine A levels, with an optimal level considered to be 100 to 400 ng/mL.

• All patients following splenectomy and liver biopsy are recommended to undergo pathomorphological examination of the spleen biopsy (surgical) material and pathomorphological examination of the liver biopsy (surgical) material [9, 40–44].

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

Comments: The histological picture of the removed spleen allows for the confirmation of the diagnosis of MDS or MDS/MPN and the detection of signs of secondary iron overload.

• All patients after splenectomy with liver biopsy, when blast cell infiltration or another disease is suspected, are recommended to undergo pathomorphological examination of the spleen biopsy (surgical) material and liver biopsy specimen using immunohistochemical methods [9, 45–47].

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

Comments: Pathomorphological examination of spleen and liver biopsy (surgical) material using immunohistochemical methods in MDS or MDS/MPN is performed on paraffin block sections of the spleen and liver. CD34 antibodies are used for visualization and semi-quantitative evaluation of cells with blast morphology; monocytes are identified using CD14, CD16, and lysozyme. When other diseases are suspected, the panel of immunohistochemical markers depends on the differential diagnostic search.

2.4 Instrumental Diagnostics

Instrumental diagnostic methods allow for the differential diagnosis of cytopenic syndrome and cytosis, as well as the detection of comorbid pathology in MDS [1–5].

• All patients with suspected MDS and MDS/MPN are recommended to undergo a comprehensive ultrasound examination of the abdominal organs, renal ultrasound, thyroid and parathyroid ultrasound, comprehensive pelvic ultrasound (transvaginal and transabdominal) for women, prostate ultrasound, and echocardiography to determine comorbid conditions [1, 120].

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

Comments: Ultrasound examination of the abdominal cavity and retroperitoneum (liver, spleen, pancreas, gallbladder, lymph nodes, including peripheral ones) is performed when MDS or MDS/MPN is suspected, and during treatment to detect hepatosplenomegaly, lymphadenopathy, and pathology of other vital organs. To rule out thyroid pathology (which may present with anemia and thrombocytopenia), an ultrasound of the thyroid and parathyroid glands is performed. Breast ultrasound or mammography is performed to rule out neoplasms, and echocardiography is performed to assess the cardiovascular system when MDS is suspected and during the course of treatment.

• All patients with suspected MDS and MDS/MPN are recommended to undergo: brain MRI or brain CT to rule out CNS pathology (specifically CNS neoplasms), which may be accompanied by cytopenic syndrome [62].

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

• All patients with suspected MDS or MDS/MPN, as well as at all subsequent stages of treatment, are recommended to undergo: Computed tomography of the chest organs (to rule out inflammatory and non-inflammatory lesions of the lungs and mediastinum) [1].

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

• All patients with suspected MDS or MDS/MPN are recommended to undergo esophagogastroduodenoscopy (EGD) with any test for Helicobacter pylori: microbiological (culture) examination of gastric wall biopsy specimens for Helicobacter pylori, or microbiological (culture) examination of gastric mucosal biopsy specimens for Helicobacter pylori, or molecular biological examination of gastric mucosal biopsy specimens for Helicobacter pylori, or detection of Helicobacter pylori DNA in gastric mucosal biopsy specimens by PCR, or microscopic examination of gastric material for Helicobacter pylori, in order to rule out chronic diseases or neoplasms of the esophagus, stomach, and duodenum [1].

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

• All patients with suspected low-risk MDS (see section 7.1 of these guidelines) or MDS/MPN are recommended to undergo colonoscopy to rule out chronic gastrointestinal diseases and neoplasms that may be accompanied by cytopenic syndrome [1].

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

• All patients with suspected MDS or MDS/MPN, as well as during therapy, are recommended to undergo electrocardiography to assess the state of the cardiovascular system [1].

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

2.5 Other Procedures

• All patients with MDS and MDS/MPN are recommended to undergo lifelong regular follow-up by a hematologist [1, 118].

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

Comments: the follow-up schedule is not standardized and is set individually by each physician for each patient depending on the MDS or MDS/MPN subtype, patient age, and comorbid conditions.

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

Myelodysplastic syndromes are an extremely heterogeneous group of disorders, ranging from forms with a nearly normal life expectancy to variants with a clinical course similar to AML. Selecting personalized, risk-adapted therapy is mandatory given this high degree of heterogeneity. Prognostic factors can be divided into those related to patient characteristics and those determined by the features of the specific MDS variant.

Unfortunately, it must be acknowledged that there is currently no universal prognostic scoring system that incorporates all parameters relevant to MDS (morphological subtype, LDH, β2-microglobulin, ferritin, etc.); therefore, when deciding on therapeutic tactics, prognosis can be assessed using the IPSS-R scale (see section 7.1 of these guidelines). Evidence of the efficacy and safety of available therapeutic options has been obtained from clinical trials in which patient stratification was based on the IPSS system, and over the past decade, on IPSS-R. As a result, all current practical treatment recommendations are based on patient stratification according to IPSS and IPSS-R. Given the 20–30% discrepancy in risk group assignment between the IPSS, WPSS, and IPSS-R scales, it is advisable to use a single scale to avoid discrepancies in determining the prognosis of MDS. The Russian expert community recommends using IPSS-R as the baseline tool for determining risk groups and selecting treatment tactics. It should also be emphasized that to gain a clearer understanding of the disease course and select optimal therapeutic interventions, it is strongly recommended to perform repeat evaluations of patients rather than relying on isolated results. Risk scales are presented in Appendix G1 of these guidelines [1, 2, 30, 63, 64]. In 2022, a new prognostic scale, IPSS-M, was introduced, which is based on IPSS-R criteria with the addition of molecular genetic analysis data for 31 genes (16 core and 15 secondary) [155]. Given the lack of technical capability for molecular genetic analysis on this scale in routine clinical practice, the Russian expert community considers the implementation of this scale for selecting treatment tactics to be premature,

For patients with a karyotype that could not be evaluated due to technical reasons, the choice of therapeutic regimen should take into account the WHO morphological classification of MDS, the bone marrow blast count and its dynamics, bone marrow cellularity, and the severity of cytopenias [1].

The choice of therapy depends on the patient's age, MDS subtype, risk group, presence and severity of comorbidities, and availability of an HLA-compatible donor. Currently, it is recommended to use the IPSS-R scale for a more accurate determination of disease prognosis.

There are several approaches to the treatment of MDS, taking into account the pathogenesis and heterogeneity of the disease, but the most effective and globally recognized are:

– supportive care:

– blood component replacement therapy (donor red blood cell components, platelet concentrate, fresh frozen plasma),

– iron chelation therapy,

– hematopoietic stimulants (antianemic agents, colony-stimulating factors, hemostatic agents),

– antibacterial therapy;

– antineoplastic chemotherapy:

– intensive chemotherapy regimens for AML,

– low-dose chemotherapy,

– antineoplastic agents: antimetabolites; pyrimidine analogues

(hypomethylating agents);

– immunosuppressive and immunomodulatory therapy:

– ATG**,

– #CsA**,

– lenalidomide**,

– splenectomy;

– allogeneic hematopoietic stem cell transplantation (allo-HSCT) [1–5].

Allo-HSCT is the only curative biological treatment option; however, this procedure can be successfully performed in only 5–10% of cases due to the lack of an HLA-identical donor, patient performance status and age, as well as specific features of MDS or MDS/MPN.

In the treatment of patients with MDS, a combination of the above therapies, as well as their sequential administration due to treatment failure and/or disease progression, is permitted. For example, a patient may receive IST, and upon progression to MDS-EB-1 or EB-2, be prescribed hypomethylating agents (pyrimidine analogues) or chemotherapy.

The heterogeneity of MDS also complicates the assessment of treatment response. In 2000, the International Working Group (IWG) defined standardized response criteria for MDS. These were subsequently revised and updated in 2006 (see Appendix G2). The IWG criteria define various aspects of response tailored to treatment goals and include complete remission (CR) and partial remission (PR), cytogenetic response, hematological improvements, and quality of life. The use of these criteria is recommended both for clinical practice and in clinical trials [65].

• MDS patients belonging to the low and intermediate-1 risk groups according to the IPSS scale (see section 7.1 of these guidelines) and very low and low risk groups according to the IPSS-R scale (see section 7.1 of these guidelines) with asymptomatic cytopenia are not recommended to receive specific treatment; instead, active surveillance ("watch and wait" strategy) is indicated to monitor disease progression and initiate specific therapy when necessary [1–5].

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

Comments: adult patients with low-risk primary MDS presenting with asymptomatic cytopenia that does not require donor blood component replacement therapy do not need treatment and only require regular follow-up. The watch-and-wait strategy may change in the future if safe, less aggressive, or targeted therapies capable of influencing the disease prognosis are developed. It must be emphasized that patients and their families should understand that the safety of the observational approach depends on the regularity of monitoring. The goal of active surveillance is early recognition of signs of worsening cytopenia, development of transfusion dependence, an increase in the blast cell count in the blood or bone marrow, as well as assessment of karyotypic evolution.

• Active surveillance is recommended for patients with MDS/MPN. Therapy for CMML should be initiated when the disease becomes symptomatic or progressive: specifically, treatment is initiated at a hemoglobin level <100 g/L, bone marrow blasts >5%, platelets <10×10⁹/L, progressive leukocytosis (>30×10⁹/L), extramedullary involvement (skin lesions, pleural/pericardial effusion, lymphadenopathy), constitutional symptoms (weight loss, fever), and symptomatic splenomegaly or splenomegaly palpable at ≥ 5 cm below the left costal margin. Initiation of therapy requires the presence of 2 or more CMML symptoms (4, 5).

  Level of recommendation C (evidence level – 5)

3.1. Conservative management

• All patients with MDS and MDS/MPN presenting with anemic complaints and symptoms of hypoxemia at Hb <85–80 g/L are recommended to receive replacement therapy with red blood cell components of donor blood (RBCCDB) to compensate for/relieve anemia symptoms [66].

GCR ALOE 2Grade of Recommendation A (Level of Evidence – 2)

Comments: data on the indications for prescribing red blood cell components of donor blood in MDS are limited. Transfusion dependence on red blood cell components in patients with MDS is associated with a poor prognosis and is generally explained by a more aggressive disease course and transfusion-related toxicity. A hemoglobin level below 90 g/L for men and 80 g/L for women is an independent prognostic factor associated with reduced overall survival and a high risk of fatal cardiovascular complications.

No specific hemoglobin level can be recommended as a threshold and defining indication for transfusion therapy. The decision should be made based on the patient's existing symptoms and comorbidities. Formalizing the above, the Expert Group for the Diagnosis and Treatment of MDS recommends transfusions of red blood cell components of donor blood when hemoglobin drops below 85–80 g/L and clinically significant symptoms of anemia (hypoxemia) are present. RBCCDB transfusions must be performed after determining the phenotype for C, c, E, e, C ^w, K, k antigens and detecting alloantibodies to red blood cells.

• Patients with MDS and MDS/MPN who develop critical thrombocytopenia (<10–20×10⁹/L) are recommended to receive replacement therapy with platelet concentrates for the prevention of hemorrhagic complications, or in their presence and at higher platelet counts, to stop hemorrhagic complications [1–5].

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

Comments: the platelet count at which patients with MDS and MDS/MPN develop hemorrhagic complications is not clearly defined and varies from patient to patient. Available data on the indications for platelet concentrate transfusions in MDS and MDS/MPN are extremely limited.

Prophylactic platelet transfusion is recommended for patients with a platelet count below 10.0×10⁹/L or below 20.0×10⁹/L in the presence of any risk factor for bleeding (fever, infection, rapid platelet drop, invasive procedures). Long-standing thrombocytopenia without a hemorrhagic syndrome does not require regular prophylactic platelet concentrate transfusions.

• For MDS patients in the low and intermediate-1 risk groups according to the IPSS scale and the very low, low, and intermediate risk groups according to the IPSS-R scale (see section 7.1 of these guidelines); all candidates for allo-HSCT; MDS patients in the intermediate-2 and high risk groups according to the IPSS and in the intermediate, high, and very high risk groups according to the IPSS-R upon achieving MDS remission, as well as patients from the MDS/MPN group after transfusion of 10–20 doses of RBC suspension, with serum ferritin levels exceeding 1000 ng/ml, it is recommended to administer iron chelation therapy with the iron-chelating agent deferasirox** to eliminate excess iron accumulation [67–73].

GCR BESL 2Grade of Recommendation B (Level of Evidence – 2

Comments: secondary iron overload invariably develops in patients receiving regular RBC suspension transfusions. One unit of RBC suspension contains 200 to 250 mg of iron, and overload may occur after as few as 10–20 transfusions. According to Russian and international publications, a statistically significant decrease in OS has been demonstrated in the group of patients with iron overload associated with transfusion dependence. An indirect biochemical marker of iron overload is conventionally considered to be an increase in serum ferritin levels above 1000 ng/ml. Exceeding this threshold clearly correlates with limited OS (HR 52.4; p <0.0001) and an increased risk of transformation to AML (HR 6.6; p <0.0001).

Therapy with an iron-chelating agent should be considered a necessary option for transfusion-dependent patients with MDS-SLD, MDS-RS, MDS-MLD, and MDS with del(5q). Ferritin values must be determined at the onset of the disease and monitored dynamically every 3 months. Ferrokinetic studies are preferably performed no earlier than 10–14 days after the last RBC suspension transfusion, outside of an infectious episode. MDS patients who are potential candidates for allo-HSCT also undergo iron-chelating agent therapy in the pretransplantation period and after allo-HSCT if signs of iron overload persist.

For patients with MDS-U upon achieving clinical and hematological remission and the presence of signs of secondary iron overload, the prescription of iron-chelating agents (chelation therapy) is possible.

Recommended starting dose of deferasirox**:

1. Dispersible tablet – 20 mg/kg/day, and in case of severe iron overload – 30 mg/kg/day. The dose is rounded to the nearest whole tablet size (125, 250, and 500 mg).

2. Film-coated tablet – 14 mg/kg/day, and in case of severe iron overload – 21 mg/kg/day. The dose is rounded to the nearest whole tablet size (90, 180, and 360 mg).

Monitoring of deferasirox** toxicity is carried out monthly, and efficacy monitoring once every 3 months, focusing on the ferritin level, preferably in combination with blood CRP and transferrin saturation. The dose is recalculated every 3–6 months with an increase in case of therapy failure, and a reduction if the ferritin level drops below 1000 ng/ml and/or signs of drug toxicity develop. If ferritin drops below 500 ng/ml, the drug is discontinued.

• For MDS patients in the low and intermediate-1 risk groups according to the IPSS scale and the very low, low, and intermediate risk groups according to the IPSS-R scale (see section 7.1 of these guidelines), as well as MDS/MPN patients, especially CMML-0, from the low and intermediate-1 risk groups, MDS/MPN-U, MDS/MPN-unclassifiable with endogenous erythropoietin preferentially <200 IU/ml, but taking into account the results of international clinical trials <500 IU/ml and hemoglobin <100 g/l, it is recommended to administer therapy with other antianemic drugs: #epoetin alfa**, #epoetin beta**, #darbepoetin alfa** (dosages – see Appendix A3.2) in order to increase hemoglobin levels and reduce dependence on RBC suspension transfusions [5, 74–77].

Level of Evidence CGrade of Evidence 5Level of Evidence C (Grade of Evidence – 5)

Comments: regarding IPSS low- and intermediate-1 risk MDS, one of the treatment approaches for refractory anemias is the administration of ESAs. The use of other anti-anemic agents (#epoetin alfa**, #epoetin beta**, #darbepoetin alfa**) helps increase hemoglobin concentration, improve patients' quality of life, and eliminate or reduce the need for RBC transfusion support. The response rate to ESA monotherapy in MDS, without accounting for endogenous EPO levels, is low and does not exceed 20%. ESAs should be prescribed only after measuring the concentration of endogenous EPO. Thus, when the concentration is less than 500 mIU/mL and RBC transfusion frequency is <2 doses/month, the efficacy is about 60%. When the serum EPO content is greater than 500 mIU/mL, EPO therapy (other anti-anemic agents) has low efficacy (~10%). In refractory anemia with ring sideroblasts, EPO (other anti-anemic agents) is not prescribed. However, if histological examination shows that the erythroid lineage is of normal size or even expanded, ESA therapy is administered.

Recommendations on the administration of ESAs are presented in Appendix A3.2.

Upon reaching the target Hb level of 110–120 g/L, the dose of ESAs (other anti-anemic agents) is reduced and subsequently discontinued if hemoglobin levels remain stable.

In the absence of a response after increasing the dose of EPO (other anti-anemic agents) and/or adding G-CSF for 6–8 weeks, therapy is discontinued.

Thus, according to the expert community, patients with IPSS low- and intermediate-1 risk MDS (see section 7.1 of these guidelines), with moderate and severe anemia (hemoglobin <100 g/L), low endogenous EPO levels (<500 mIU/mL), and/or limited transfusion requirements (less than 2 units of red blood cell suspension per month) should start therapy with #epoetin alfa** or #epoetin beta** at a starting dose of 30–40 thousand IU per week, or use equivalent doses of #darbepoetin alfa** (150–300 mcg/week) comparable in clinical efficacy to #epoetin alfa** or #epoetin beta** [76, 77].

For MDS-MLD and MDS-RS patients from the IPSS intermediate-2 and high-risk groups, and the IPSS-R intermediate-, high-, and very high-risk groups, administration as supportive therapy during the inter-cycle period, during chemotherapy or hypomethylating therapy, is also possible.

• In MDS patients with failure of therapy using other anti-anemic agents such as ESAs in monotherapy, it is recommended to add a colony-stimulating factor to the therapy to increase the efficacy of ESA therapy (other anti-anemic agents) [5, 78–80, 167].

Level of Evidence AGrade of Evidence 2Level of Recommendations A (Grade of Evidence – 2)

Comments: the probability of response to combination therapy with other anti-anemic agents (ESAs) and colony-stimulating factors (G-CSF), in particular, is higher in patients with low endogenous EPO levels (<500 mIU/mL) and limited transfusion requirements (<2 units of red blood cell components per month). In the presence of two unfavorable features, the response probability is 7%, one feature is 23%, and in their absence, it is 74%.

It should be emphasized that the combined use of other anti-anemic agents (ESAs) and a colony-stimulating factor (G-CSF) is most effective in MDS-RS patients with no response to ESA monotherapy. Colony-stimulating factor (G-CSF) #filgrastim** is administered subcutaneously at 1 to 2 mcg/kg 1–2 times a week for 6–8 weeks, the dose is selected individually, keeping the leukocyte count below 10 x 10⁹/L [5, 167].

During both standard and low-dose chemotherapy, G-CSF (colony-stimulating factors) can be used in case of expected prolonged neutropenia as supportive therapy in MDS patients.

G-CSF monotherapy (colony-stimulating factors) is currently not considered an independent treatment for neutropenia in MDS patients.

• For all MDS patients without deletion of the long arm of chromosome 5 with transfusion-dependent anemia from the IPSS-R very low, low, and intermediate risk groups, with no response to ESAs or who do not meet the criteria for ESA administration, luspatercept therapy is recommended [123, 124].

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

Comment: the efficacy and safety of luspatercept were studied in MDS patients with ring sideroblasts from the IPSS-R very low, low, and intermediate risk groups with transfusion-dependent anemia who did not achieve a response to ESA treatment or did not meet the criteria for their administration in the Phase 3 randomized MEDALIST trial [124]. Patients were randomized into two groups receiving luspatercept (at doses from 1.0 mg/kg to 1.75 mg/kg body weight) or placebo, administered subcutaneously every 3 weeks. The proportion of patients achieving RBC transfusion independence for at least 8 weeks during weeks 1 through 24 of the study was 38% in the luspatercept group and 13% in the placebo group (p < 0.001). The recommended starting dose of luspatercept is 1 mg/kg subcutaneously every 3 weeks. In the absence of a response in the form of increased hemoglobin and decreased RBC transfusion dependence, the dose should be increased to 1.33 mg/kg subcutaneously. If no response is observed at a dose of 1.33 mg/kg, the dosage should be increased to 1.75 mg/kg. Dose escalation must not be performed more frequently than once every 6 weeks (two administrations), and the maximum dosage must not exceed 1.75 mg/kg once every 3 weeks. If a response is achieved (increase in hemoglobin or decrease/absence of RBC transfusion dependence), luspatercept therapy is continued at the effective dose.

Based on the results of the Phase 3 randomized COMMANDS study, the efficacy of luspatercept in the 1st line of therapy was demonstrated in 59% of MDS patients from the very low, low, and intermediate risk groups without deletion of the long arm of chromosome 5, including patients without ring sideroblasts. The drug was administered at a standard dose of 1 mg/kg body weight, subcutaneously, every 3 weeks, with the possibility of dose escalation in the absence of a response up to 1.75 mg/kg every 6 weeks [125, 126].

• For patients with low-risk MDS without unfavorable karyotypic abnormalities or stromal fibrosis of any degree, whose leading symptom is clinically significant thrombocytopenia, potentially of immune origin, it is recommended to consider prescribing other systemic hemostatics (#eltrombopag** 50 to 150 mg orally, once daily, or #romiplostim** 500–750 mcg subcutaneously once a week) to increase the platelet count, reduce dependence on platelet concentrate transfusions, and diminish manifestations of hemorrhagic syndrome [24, 83–89].

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

Comments: several randomized trials have been conducted, the results of which demonstrate the efficacy of this type of therapy in low-risk MDS patients in terms of increasing platelet counts and reducing manifestations of hemorrhagic syndrome in 46–65% of cases. However, in high-risk MDS patients, particularly MDS with excess blasts, the addition of #eltrombopag** to azacitidine therapy reduced the efficacy of the latter and increased the rate of progression to AML. In low-risk MDS patients receiving #romiplostim** therapy, the probability of progression to AML within 5 years was comparable to the control group—12% and 11%.

To resolve the issue of prescribing other hemostatic agents, it is necessary to obtain a BM histological specimen (trephine biopsy) and perform a pathological and anatomical examination of the BM biopsy (surgical) material using immunohistochemical (IHC) methods (with Gomori staining) to determine the presence of stromal fibrosis.

• In CMML patients, autoimmune manifestations, including immune-mediated thrombocytopenia, may develop in 20–30% of cases. For patients with the myelodysplastic variant of CMML from the low-risk group with thrombocytopenia, likely of immune origin, it is recommended to prescribe other systemic hemostatics (#eltrombopag** 100 to 300 mg orally, once daily, average dose 150 mg) to increase the platelet count, reduce dependence on platelet concentrate transfusions, and diminish manifestations of hemorrhagic syndrome [127].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: the results of the phase II clinical trial NCT02323178 showed good tolerability of #eltrombopag** and efficacy in terms of increasing platelet counts in 46.7% of CMML patients [127].

• For MDS patients in the low and intermediate-1 risk groups according to the IPSS and the low and intermediate risk groups according to the IPSS-R (see section 7.1 of these guidelines) with hematopoietic hypoplasia, normal karyotype, favorable or intermediate risk abnormalities, excluding 7q-, iso(17q), it is recommended to administer immunosuppressive therapy (IST): #cyclosporine** (#CSA**) at a dose of 5 mg/kg/day in 2 divided doses, orally, with monitoring of #cyclosporine** blood serum concentration as monotherapy or in combination with other drugs to achieve a positive response in immune cytopenia, including complete clinico-hematological remission [1, 90, 154].

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

Comments: certain similarities in the clinical and morphological manifestations of hypoplastic MDS and AA, proven immune mechanisms of cytopenia development in MDS with hematopoietic hypoplasia, as well as clinical observations regarding the effect of immunosuppressive therapy in individual patients, formed the basis for testing #ATG** as a therapeutic method in two phase 2 and 3 clinical trials. According to the combined data of these projects, 30% of patients with a bone marrow blast count of less than 5% responded to therapy. In the case of RARS or RAEB, the probability of response is negligible. As a result, MDS patients in the IPSS low-risk group, with hypoplastic bone marrow according to pathomorphological examination, a short duration of prior transfusion therapy, and the presence of HLA-DR15, have a high probability of response to IST. The best results are provided by combination therapy with #ATG** and #CSA**. Also, considering the similarity in the pathogenesis of MDS with hematopoietic hypoplasia and aplastic anemia, it is possible to add other systemic hemostatics, in particular #eltrombopag** at a dose of 150 mg/day orally, to #CSA** therapy [127].

Based on available data, combined IST with #ATG** and oral #CSA** for 6 months should be considered as the treatment of choice for MDS patients with a bone marrow blast count of less than 5%, normal karyotype or trisomy 8, transfusion dependency of less than 2 years, who are not candidates for growth factor therapy or in whom such therapy has proven ineffective, with the HLA-DR15 genotype, minimal PNH clone, and a STAT3 gene mutation.

Based on the experience of Russian research centers, it is advisable to recommend #CSA** monotherapy for the same category of patients, as well as for patients with favorable karyotype variants and trisomy 8. IST in MDS patients can be initiated by prescribing #CSA** at a dose of 5 mg/kg/day orally, divided into 2 doses, with monitoring of the drug's serum concentration and blood biochemical parameters. In case of its ineffectiveness for 3–6 months, a course of #ATG** at a dose of 20 mg/kg/day on days 1–5 as a prolonged intravenous infusion [1] followed by the resumption of #CSA** is advisable. A possible treatment option is to start therapy with the administration of #ATG** at a dose of 20 mg/kg/day for 5 days [1] or 40 mg/kg/day for 4 days [90], followed by the administration of #CSA** on day 14 from the start of IST. If there is no response to combination IST for 6–9 months and no disease progression in the form of an increase in blasts and the appearance of new cytogenetic changes, splenectomy or a repeat course of #ATG** may be performed. The total duration of therapy for patients who responded to #CSA** should be at least 24 months. IST is most justified in hematopoietic hypoplasia or uneven cellularity with areas of bone marrow hypoplasia or aplasia. In MDS-EB-1 with favorable karyotype abnormalities and hematopoietic hypoplasia, IST may also be prescribed, but only after consultation at a federal center. If IST is ineffective and marked transfusion dependence on blood components persists, addressing the possibility of allogeneic HSCT is advisable.

• For MDS patients with an isolated deletion of the long arm of chromosome 5 (5q- syndrome) when ESA therapy is unfeasible or ineffective, it is recommended to administer lenalidomide** therapy to achieve complete clinico-hematological and cytogenetic remission, or any other positive response [56, 91].

GRC ALOE 2 Recommendation Grade A (Level of Evidence – 2)

Comments: clinical studies have proven the high efficacy of lenalidomide** in MDS patients with del(5q). The mechanism of action of the drug in MDS is explained by a direct cytostatic effect on the pathological clone of cells with del(5q) and a stimulating effect on normal bone marrow erythroid cells. Red blood cell transfusion independence was documented in 61% and 70% of cases (p >0.05). The median time to response was 4–6 weeks. In MDS patients without del(5q), the efficacy is somewhat lower, at 25–27% of cases.

The use of lenalidomide** is most justified in transfusion-dependent MDS patients with del(5q) (and one additional favorable abnormality, excluding aberrations of chromosomes 3 and 7) or an increased blast count of less than 10% from the IPSS low or intermediate-1 risk group who are not candidates for therapy with other antianemic drugs (ESAs) or have not benefited from them. Lenalidomide** is prescribed at a dose of 10 mg orally on days 1–21, every 28 days. If hematological or non-hematological toxicity develops, reducing the dose to 5 mg/day or 10 mg every other day is advisable; continuous administration without breaks is possible at such a dose. The optimal duration of lenalidomide** therapy is not defined, but, apparently, should be limited by the time hemoglobin levels rise to the upper limit of normal, until disease progression begins, or to a total treatment duration of 24 months in the event of a sustained response. Currently, the issues of discontinuing lenalidomide** upon achieving a sustained hematological and complete cytogenetic response should be considered individually.

Prior to initiating lenalidomide** therapy, it is advisable to test for mutations in the TP53 gene, as their presence is associated with a shorter duration of positive response and a high probability of progression to AML.

• For MDS patients from the IPSS low and intermediate-1 risk groups, or the IPSS-R very low, low, and intermediate (<3.5 points) risk groups, in the absence of unfavorable karyotype abnormalities when ESA therapy is ineffective, it is recommended to administer lenalidomide** therapy at a dose of 10 mg orally on days 1 to 21, every 28 days, with response assessment after 4 treatment cycles, to achieve complete clinico-hematological remission, or any other positive response as monotherapy or in combination with standard doses of ESAs [81, 82].

GRC BLOE 2 Recommendation Grade B (Level of Evidence – 2)

Comments: when ESAs are ineffective, lenalidomide** ensures red blood cell transfusion independence in 20–30% of cases, while the combined use of standard-dose ESAs with lenalidomide** increases efficacy to 39–46%. According to a randomized phase III study involving 131 low-risk MDS patients without 5q deletion, refractory to ESAs and dependent on red blood cell transfusions, an erythroid response was obtained with lenalidomide** monotherapy at a daily dose of 10 mg orally on days 1 to 21, every 28 days, after 4 treatment cycles in 23.1% of cases, and with combination therapy of lenalidomide** at the same dose combined with ESAs (#epoetin beta** - 60,000 IU/week) in 39.4% (p=0.044). The median response duration was 18.1 and 15.1 months, respectively (p=0.47). Side effects were similar in both groups. A low serum EPO level is a predictor of achieving an erythroid response. A similar phase III clinical trial comparing single-agent lenalidomide with combination therapy of lenalidomide and #epoetin alfa** for 16 weeks demonstrated comparable efficacy rates of 32.3% and 46.5%, respectively. Lenalidomide** therapy is advisable when the absolute neutrophil count is >0.5x10⁹/L and platelet count is >50x10 ⁹/L.

• For patients with MDS/MPN: CMML-0 or MDS/MPN with ring sideroblasts and thrombocytosis in the presence of red blood cell transfusion dependency and lack of response or inability to prescribe ESAs, it is recommended to prescribe #lenalidomide** at a daily dose of 10 mg orally on days 1 to 21, every 28 days [128-130].

__(UC R)__ C__(LEL)__ 4Level of Evidence Recommendation - C (Level of Evidence – 4)

Comments: prescribing #lenalidomide** to patients with MDS/MPN-RS-T in the presence of transfusion-dependent anemia led to hematological improvement in 42-50% of cases, with a median response duration of 10-11 months [128, 130].

• For MDS patients with or without MDS-EB with adverse karyotypic abnormalities stratified into the intermediate-2 and high-risk groups by the IPSS, or intermediate (>3.5 points), high, and very high-risk groups by the IPSS-R (see Section 7.1 of these guidelines), with CMML-1, CMML-2, aCMML, MDS/MPN-unclassifiable, as well as low-risk MDS patients in case of failure of first- and second-line therapy, therapy with pyrimidine analogues – azacitidine** or decitabine – is recommended to achieve remission or another positive response [92–96, 131–134].

GGR BLOE 1Grade of Recommendation B (Level of Evidence – 1)

Comments: azacitidine** and decitabine belong to the original class of pyrimidine analogues, namely hypomethylating agents or DNA methyltransferase inhibitors, an enzyme responsible for the methylation of newly synthesized DNA.

In light of the lack of direct comparative studies between azacitidine** and decitabine, it is impossible to draw a definitive conclusion regarding the superiority of either drug.

Azacitidine** is prescribed in several regimens:

• Azacitidine** – 75 mg/m² subcutaneously once daily on days 1–7 every 28 days or

• #Azacitidine** – 75 mg/m² subcutaneously once daily 5–2–2 (the drug is administered on days 1–5 and 8–9 of the cycle, with days 6 and 7 off) every 28 days [131] – this regimen can be used for outpatient treatment when weekend administration is not possible; in this case, it is advisable to start the cycle on Monday, or

• #Azacitidine** – 75 mg/m² subcutaneously once daily on days 1–5 every 28 days [96] or

• #Azacitidine** – 75 mg/m² subcutaneously once daily on days 1–3 every 28 days [131].

The use of #azacitidine** in a 3-day regimen is preferred for low-risk MDS patients in the absence of response to 1st and 2nd line therapy, and may also be used for maintenance therapy taking into account observed hematological toxicity.

The 7-day course of azacitidine** therapy is the most preferred.

In the absence of disease progression, treatment efficacy should be evaluated after 4–6 cycles (the recommended number of cycles is at least 6). In the event of a positive response (complete, partial, or bone marrow remission, hematological improvement), therapy should be continued until the development of severe hematopoietic hypoplasia (aplasia) as a manifestation of hematological toxicity or disease progression. If a clinically significant hematological response is not achieved or MDS progression develops, a change in therapeutic tactics is indicated.

Decitabine can be used in several regimens:

• Decitabine – 20 mg/m² as a 60-minute infusion once daily on days 1–5 every 28 days or

• Decitabine – 15 mg/m² 3 times daily as a 3-hour intravenous infusion on days 1–3, every 6 weeks or

• #Decitabine – 20 mg/m² as a 60-minute infusion once daily on days 1–3 every 28 days. [131]

In the absence of disease progression, treatment efficacy should be evaluated after 4 cycles (the recommended number of decitabine cycles is at least 4). In the event of a positive response (complete, partial, or bone marrow remission, hematological improvement), therapy should be continued until the development of severe hematopoietic hypoplasia as a manifestation of hematological toxicity or disease progression. The 3-day administration regimen of #decitabine** is preferred for low-risk MDS patients in the absence of response to 1st and 2nd line therapy, as well as during maintenance therapy when hematological toxicity is detected.

The question of the duration of long-term pyrimidine analogue therapy without allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains unresolved and is under discussion in the international hematological community.

In patients with CMML-1 and CMML-2 from the intermediate-2 and high-risk groups, aCMML, MDS/MPN-T and MDS/MPN-unclassifiable, azacitidine** and decitabine demonstrated efficacy in 17–70% of cases, with complete remissions achieved in 7–45%. The best results were demonstrated in the presence of TET2 gene mutations and the absence of ASXL1 gene mutations. In CMML, the efficacy in terms of achieving complete remissions on decitabine was slightly higher than on azacitidine**, 23% vs 10%, and the best results with decitabine therapy were obtained in myelodysplastic CMML (MD-CMML) rather than myeloproliferative CMML (MP-CMML). [131, 132, 133, 134]

The administration regimens for azacitidine** and decitabine are identical for MDS and MDS/MPN.

• For MDS patients with excess blasts from the high and very high-risk groups by IPSS-R in the presence of adverse karyotypic abnormalities, CMML-2 with adverse karyotypic abnormalities from the intermediate-2 and high-risk groups by CPSS, aCMML, and MDS/MPN-u with a blast count >10% and the presence of adverse karyotypic abnormalities, azacitidine** therapy in combination with another antineoplastic agent, #venetoclax**, is recommended as induction therapy, or upon failure of 1st-line therapy, or upon relapse [135, 136, 138, 139, 144].

GPP CLEL 4Level of Evidence Recommendation C (Level of Evidence – 4)

Comments: the high efficacy in AML treatment of the combination of #venetoclax** (a bcl-2 inhibitor) with azacitidine** led to the study of this combination in patients with MDS and MDS/MPN, which increased efficacy up to 87%, with complete remission (CR) achieved in 35% of cases (azacitidine** and #venetoclax**), which is especially important for high-risk MDS and MDS/MPN patients scheduled for allo-HSCT.

Recommended treatment regimens:

#Venetoclax**, orally, day 1 – 100 mg, day 2 – 200 mg, days 3–14 – 400 mg, every 28 days in combination with:

Azacitidine** 75 mg/m2, subcutaneously, days 1–7, every 28 days or

#Azacitidine** 75 mg/m2, subcutaneously, days 1–5, every 28 days or

For MDS/MPN, it is advisable to start the 1st cycle when the leukocyte count is <10–20x10⁹/L with dose escalation of #venetoclax**.

#Venetoclax** is metabolized primarily by cytochrome P450 family IIIA (CYP3A) isoenzymes. When #venetoclax** is administered concomitantly with moderate and strong CYP3A inhibitors, a dose adjustment of the drug is required in accordance with the instructions.

In the event of severe neutropenia and infectious complications, the dose and duration of #venetoclax** administration may be reduced.

• For MDS patients with excess blasts from the high and very high-risk groups by IPSS-R in the presence of adverse karyotypic abnormalities, CMML-2 with adverse karyotypic abnormalities from the intermediate-2 and high-risk groups by CPSS, decitabine therapy in combination with another antineoplastic agent, #venetoclax**, is recommended as induction therapy, or upon failure of 1st-line therapy, or upon relapse [136, 144].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: the high efficacy in AML treatment of the combination of #venetoclax** (a bcl-2 inhibitor (L01XX Other antineoplastic agents)) with decitabine led to the study of this combination in patients with MDS and MDS/MPN, which increased efficacy up to 74%, with CR achieved in 47% of cases, which is especially important for high-risk MDS and CMML-2 patients scheduled for allo-HSCT.

Recommended treatment regimens:

#Venetoclax**, orally, day 1 – 100 mg, day 2 – 200 mg, days 3–14 – 400 mg, every 28 days in combination with:

Decitabine 20 mg/m², intravenously, days 1–5, every 28 days or

For MDS/MPN, it is advisable to start the 1st cycle when the leukocyte count is <10–20x10⁹/L with dose escalation of #venetoclax**.

In the event of severe neutropenia and infectious complications, the doses and duration of #venetoclax** administration may be reduced.

• For MDS patients with excess blasts from the high and very high-risk groups by IPSS-R in the presence of adverse karyotypic abnormalities, CMML-2 with adverse karyotypic abnormalities from the intermediate-2 and high-risk groups by CPSS, with the presence of adverse karyotypic abnormalities, low-dose #cytarabine** therapy in combination with another antineoplastic agent, #venetoclax**, is recommended as induction therapy, or upon failure of 1st-line therapy, or upon relapse [140, 165].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: high efficacy in the treatment of AML with the combination of #venetoclax** (a bcl-2 inhibitor (L01XX Other antineoplastic agents)) and low-dose #cytarabine** reached 67%, despite the fact that one-third of patients had received hypomethylating agent therapy at previous stages of treatment for high-risk MDS-EB. Considering this fact, the expert panel considers it appropriate to recommend prescribing the combination of #venetoclax** (a bcl-2 inhibitor (L01XX Other antineoplastic agents)) and low-dose #cytarabine** for patients with MDS-EB2 and CMML-2 with unfavorable karyotype abnormalities, as well as in case of resistance to ongoing therapy, with a duration of #venetoclax** administration for 14 days, similarly to combination therapy courses with hypomethylating agents.  

Recommended treatment regimens:

#Venetoclax**, orally, day 1 - 100 mg, day 2 - 200 mg, day 3 - 400 mg, days 4–14 - 600 mg, every 28 days in combination with:

#Cytarabine** 20 mg/m², once daily, subcutaneously, days 1–10, every 28 days, or

#Cytarabine**, 10 mg/m2 × 2 times a day, subcutaneously, days 1–10, every 28 days. [140, 165, 166].

Further studies investigating the efficacy of #venetoclax** in various combinations for MDS are currently underway.

#Venetoclax** is metabolized primarily by cytochrome P450 family IIIA (CYP3A) isoenzymes. When #venetoclax** is administered concomitantly with moderate and strong CYP3A inhibitors, a dose adjustment of the drug is required in accordance with the instructions.

In the event of severe neutropenia and infectious complications, the doses and duration of administration of #cytarabine** and #venetoclax** may be reduced. 

• For patients with intermediate-2 and high-risk MDS according to the IPSS and intermediate, high, and very high-risk MDS according to the IPSS-R, patients with MDS/MPN: CMML-2 with unfavorable karyotype abnormalities, aCMML, and MDS/MPN-u with 10% to 19% blast cells as induction therapy in case of inefficacy of low-dose or standard chemotherapy or disease progression, it is recommended to administer a course of low-dose #cytarabine** and #idarubicin** with hypomethylating priming of decitabine or #azacitidine** (Dac-Ida-AraC, Aza-Ida-AraC) in order to achieve a positive response, including complete clinical and hematological remission [97, 98, 156].

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

Comments: performing intensive chemotherapy according to acute leukemia treatment regimens in patients with MDS is associated with moderate efficacy, prolonged myelotoxic agranulocytosises, high early mortality (~20%), and short remission duration. Hypomethylating priming before a course of low-dose #cytarabine** and #idarubicin** increases apoptosis in tumor cells and leads to an enhanced cytotoxic effect on leukemic cells. The probability of achieving CR in patients with MDS from the adverse risk category is 40–60%, with low early mortality.

The National Medical Research Center for Hematology of the Russian Ministry of Health has developed and implemented into clinical practice the Aza/Dac-Ida-AraC course: #azacitidine** 75 mg/m² subcutaneously once daily or decitabine 20 mg/m² intravenously once daily on days 1–3, #cytarabine** 10 mg/m² twice daily subcutaneously on days 4–17, #idarubicin** 3 mg/m² intravenously once daily on days 4–10. [156]. If hematopoietic aplasia, severe infectious, or hemorrhagic complications develop, it is possible to shorten the course to a total duration of 10 days (#cytarabine** is administered for 7 days on days 4–10, #idarubicin** for 5 days on days 3–8) [156].

Response assessment in the absence of disease progression is performed after the 2nd course of therapy, 28–35 days after the end of the course. Upon achieving CR, 2 courses of bone marrow consolidation are performed according to the same regimen. Patients who have no contraindications to allo-HSCT and have an HLA-matched donor should undergo allo-HSCT as early as possible

If allo-HSCT is not feasible, Aza/Dac-AraC maintenance therapy is administered for 2 years (see Appendix A3.1) [99, 156].

• For patients with MDS-EB with normal karyotype or single favorable or intermediate-risk anomalies, as well as patients with CMML-1, CMML-2, aCMML, MDS/MPN-u it is recommended to administer a course of low-dose #cytarabine** (LDAC) for therapeutic purposes [100, 141, 157, 168].

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

Comments: treatment with low-dose #cytarabine** for MDS and CMML outside the Russian Federation is administered for 14 days. In the Russian Federation, this therapy is often used in patients with MDS-EB-1 and EB-2, CMML with normo- or hypercellular bone marrow. The generally accepted regimen for low-dose cytarabine (LDAC) use in the Russian Federation is administration of the drug at a dose of 10 mg/m² twice daily subcutaneously for 28 days (21 days if neutropenia develops and therapy cannot be continued)[168]. The probability of achieving CR in patients with RAEB-2 is significantly higher if the course duration was at least 23 days. Detection, based on pathological examination of bone marrow biopsy (surgical) material, of reduced bone marrow cellularity can help adjust the choice of therapeutic approach: the duration of LDAC therapy may be reduced to 10–14 days (and the dose of #cytarabine** may be reduced to 10 mg twice daily). The intervals between cycles are 28–30 days, and therapy is continued until progression or signs of unacceptable toxicity occur, but for no more than 3 years. When 10-14-day courses are administered, they are repeated every 28-35 days. The use of LDAC is most appropriate in patients with a normal karyotype or favorable aberrations [1, 92, 100]. Therapy with #cytarabine** at various doses and durations serves as the basis for adding other antineoplastic agents.

• For patients with MDS-EB-2 who are under 60 years of age and in whom pyrimidine analogue therapy (azacitidine, decitabine) is not feasible, it is recommended to administer an induction therapy course according to "7+3" programs used in the treatment of AML, utilizing combinations of the following drugs: #cytarabine**, #daunorubicin**, #idarubicin**, #mitoxantrone** (see Appendix A3.1, as well as profile guidelines for the treatment of AML) [1–5, 101, 158–160, 164].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: therapy for MDS-EB2 according to AML treatment protocols is considered for young patients, predominantly with a normal karyotype, when hypomethylating therapy is not feasible, as preparation for allo-HSCT. If allo-HSCT is not performed, further therapy is carried out according to the AML treatment protocol [164].

• For patients with MDS/MPN with progressive leukocytosis >30x10⁹/L, anemia <100 g/L, thrombocytopenia <100x10⁹/L, bone marrow blast cell increase >5%, splenomegaly (palpable spleen +5 cm below the costal margin) or hepatosplenomegaly, presence of extramedullary involvement (skin, pleural or pericardial effusion, lymphadenopathy), presence of B-symptoms (weight loss, fever), especially in patients over 70 years of age, or with hyperleukocytosis, as preparation for the initiation of antineoplastic therapy to reduce the leukocyte count, it is recommended to use #hydroxycarbamide** [142, 143].

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

Comments: #Hydroxycarbamide** is prescribed at a dose of 1000 mg/day under the control of hemogram parameters; if no response is observed within 2 weeks, the dose is increased to 2000 mg, with possible further escalation to maintain the leukocyte count within 10x10⁹/L. #Hydroxycarbamide** is predominantly prescribed to patients with myeloproliferative CMML. Treatment may be accompanied by worsening anemia and thrombocytopenia, which requires blood transfusions and dose adjustment.

• For patients with MDS-EB with normal karyotype and hematopoietic hypoplasia when programmed (course) antineoplastic therapy is not feasible, it is recommended to administer #melphalan** therapy at 2 mg/day to achieve a positive response, including complete remission [102, 103].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: the use of low doses of #melphalan** was studied in two prospective cohort studies totaling 29 high-risk MDS patients. The overall response rate was 38–40%, with minimal toxicity noted. The probability of response to therapy was highest in patients with hypocellular bone marrow, excess blasts, and a normal karyotype.

• For patients with MDS-EB, patients with CMML, aCMML, MDS/MPN-u when azacitidine or decitabine therapy is not feasible, in case of resistance to #hydroxycarbamide** or relapse, it is recommended to administer therapy with #mercaptopurine** [1, 2].

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

Comments: in patients with MDS presenting with an increased blast cell count, #mercaptopurine** therapy may be administered. The drug is prescribed at a dose of 60 mg/m² orally in 2 divided doses on a continuous schedule, with dose adjustment or discontinuation if severe cytopenia develops. If the leukocyte count drops below 3.0×10⁹/L, the dose is reduced by 25%; if it drops below 2.0×10⁹/L, by 50%; and if it falls below 1.5×10⁹/L, the drug is discontinued until counts recover, at which point treatment can be resumed. #Mercaptopurine** therapy is generally considered exclusively as a palliative approach and may be administered at a lower dosage [1, 2].

In patients with MDS/MPN, particularly CMML, aCML, or unclassifiable MDS/MPN (MDS/MPN-U) with refractory disease or relapse, #mercaptopurine** therapy may be administered to maintain the leukocyte count within the range of 5–10×10⁹/L.

• For MDS patients in the intermediate-1 risk group with unfavorable karyotypic abnormalities, intermediate-2 or high risk according to the IPSS scale, or intermediate, high, and very high risk according to the IPSS-R scale (see section 7.1 of these guidelines), as well as MDS/MPN patients: CMML in the intermediate-2 and high risk groups according to the CPSS or molecular CPSS, aCML, and unclassified MDS/MPN aged <60–65 years in the absence of severe comorbidities, and also for patients with MDS without excess blasts from the intermediate-1 risk group by IPSS and intermediate risk group by IPSS-R younger than 40–50 years who are resistant to ongoing therapy and have significant transfusion dependence, allogeneic HSCT is recommended to achieve complete biological cure [104].

GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)

Comments: recommendations for allo-HSCT in patients with MDS are based on prospective randomized and non-randomized, as well as cohort, clinical trials. According to the International Bone Marrow Transplant Registry (IBMTR), based on an analysis of treatment outcomes in 387 adult patients with MDS who underwent allo-HSCT from an HLA-identical sibling, the cumulative transplantation-related mortality was 32% at 1 year and 37% at 3 years, the cumulative relapse rate was 17% and 23%, and overall survival (OS) was 53% and 40%, respectively. Bone marrow blast count and IPSS risk showed an inverse correlation with relapse-free survival after transplantation. Progression-free survival in low- or intermediate-1 risk IPSS patients at 5 years was 60%, in intermediate-2 risk patients 36–44%, and in high-risk patients 28–30%.

The optimal timing for allo-HSCT from an HLA-compatible donor in MDS has been determined through IBMTR clinical decision analysis. This study demonstrated that life expectancy in patients with low- or intermediate-1 risk IPSS was higher when HSCT was delayed over time but performed prior to transformation into AML. Conversely, for patients in the intermediate-2 and high-risk groups, upfront (immediate) HSCT significantly improves survival rates. Recruiting an unrelated donor in the absence of an HLA-matched related donor does not increase mortality.

Disease risk according to IPSS, age, and comorbidities assessed by the HSCT comorbidity index (HCT-CI — see Appendix G3 [105]) are the most significant clinical factors when considering allo-HSCT for a patient

In MDS/MPN (CMML-1 or CMML-2 with intermediate-2 or high risk according to CPSS or CPSS-Mol), aCML, and MDS/MPN-U with a blast count greater than 5% and unfavorable karyotypic abnormalities, the efficacy of allo-HSCT in terms of 3-year survival is 30–48%

Performing an allo-HSCT should be a joint decision made by the physician, the patient, and their family, as their attitude toward risk is decisive.

3.2. Supportive care

• All patients with MDS undergoing chemotherapy are recommended to receive antiemetic drugs for the prevention of nausea and vomiting [106, 153].

GCR CLeE 4Grade of Recommendations C (Level of Evidence – 4)

• All patients with MDS undergoing induction chemotherapy courses are recommended to receive allopurinol** for the treatment of hyperuricemia [107, 153].

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

• All patients with MDS who develop febrile neutropenia or infectious-inflammatory diseases combined with leukopenia (upper and lower respiratory tract infections, sepsis, septicemia, urinary tract infections, skin and soft tissue infections, etc.) are recommended to use piperacillin + tazobactam, cefepime**, or ceftazidime** as first-line systemic antibacterial drugs to manage infectious complications [108, 109, 153].

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

Comments: if first-line antimicrobial therapy is ineffective, its modification must be carried out taking into account the results of performed examinations (computed tomography of the chest organs, blood microbiological (culture) test for sterility, urine microbiological (culture) test for bacterial pathogens using automated seeding, etc.). The prescription of carbapenems as first-stage systemic antibacterial drugs in febrile neutropenia is justified in patients with septic shock, as well as in clinics where extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae predominate in the etiology of infections.

• All patients with MDS undergoing a course of #ATG** are recommended prophylactic administration of systemic antibacterial and antifungal drugs [1].

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

• All patients with MDS with 5q– and a platelet count >200×10⁹/L undergoing immunomodulatory therapy with lenalidomide** are recommended antiplatelet therapy due to the potential risk of thrombotic complications [111].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: if there is a history of thrombosis, adding anticoagulant therapy is advisable. During immunomodulatory therapy, thrombotic complications can develop not only at the start of treatment in the presence of thrombocytosis, but also when hemoglobin levels rise to normal values.

• All patients with MDS, prior to transfusion of donor blood components for the prevention of citrate and other reactions, are recommended to receive #calcium gluconate**, and systemic antihistamines if necessary [153].

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

• All patients with MDS in whom signs of alloimmunization are detected are recommended to receive individually matched platelet concentrates to increase transfusion efficacy [112, 153].

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

Comments: overcoming alloimmunization in patients with MDS requires a comprehensive approach that, in addition to individualized platelet matching, includes therapeutic plasmapheresis (4–5 sessions with albumin replacement) followed by transfusion of high-dose platelet concentrates (12–16 doses).

• All patients with MDS whose condition prevents adequate natural nutrition are recommended to receive energy and plastic substrates via enteral and/or parenteral nutrition [113, 114, 153]

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

Comments: malnutrition is a compounding factor during cytostatic therapy and allo-HSCT. Total daily energy requirements for enteral and parenteral nutrition in patients over 18 years of age are calculated based on ideal body weight, including in the presence of obesity, according to the Harris-Benedict equation (25–30 kcal/kg, protein 1.2–1.5 g/kg/day), also taking into account coefficients that increase or decrease the body's energy requirements, for example, in intestinal graft-versus-host disease (GVHD) — protein 1.5–2.0 g/kg/day — and the amount of natural nutrition intake. The criterion for discontinuing nutritional support is the restoration of natural nutrition to more than 60% of the required daily needs for 3 consecutive days.

3.3. Surgical treatment

• Patients with low-risk MDS (see section 7.1 of these guidelines) with hematopoietic hypoplasia who are refractory to immunosuppressive therapy (IST), or patients with signs of autoimmune anemia or thrombocytopenia in combination with MDS, or MDS patients with splenomegaly, are recommended to undergo splenectomy for diagnostic and therapeutic purposes [1, 116].

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

Comments: splenectomy in patients with MDS is rarely performed in EU countries, mostly in patients with severe thrombocytopenia. In the Russian Federation, experience has been accumulated with splenectomy performed in 33 patients with MDS. The procedure was most frequently performed in cases of hematopoietic hypoplasia based on bone marrow histological examination (75%). In 16 (48%) cases, combined IST was administered prior to splenectomy. In 6 (18%) cases, splenomegaly exceeding 15×8 cm was documented. As a beneficial effect of splenectomy, 16 (48%) patients showed a reduction in transfusion dependence.

Splenectomy should preferably be performed laparoscopically.

• For patients with MDS/MPN: CMML in the low and intermediate-1 risk groups according to the CPSS or CPSS-mol scale (see section 7.1 of these guidelines), with splenomegaly, signs of splenic infarction or cytopenia limiting chemotherapy or of immune origin, as well as prior to allo-HSCT when organomegaly extends 20 cm or more below the costal margin, splenectomy is recommended for therapeutic purposes [152].

GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)

Comments: splenectomy in patients with MDS/MPN may be complicated by bleeding, thrombosis, and infectious complications in the perioperative period. Splenectomy should preferably be performed laparoscopically.

It should be noted that the patient may present with atypical disease manifestations, as well as a combination of a specific disease with other pathologies, which may dictate changes by the attending physician in the algorithm for choosing optimal diagnostic and treatment tactics.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

• All patients with MDS are recommended to undergo medical rehabilitation, which includes effective pain management, nutritional support, psychological well-being, and the highest possible physical functioning at all stages of treatment and supportive care [117].

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

Comments: medical rehabilitation in the management of patients with MDS is part of supportive care aimed at reducing complications, maximizing physical, emotional, and social needs, and improving the quality of life of patients and their families. Rehabilitation principles must be based on the International Classification of Functioning, Disability and Health (ICF) developed by the WHO in 2002. The main conditions include the work of a multidisciplinary team (MDT), early initiation, a patient-centered approach, long-term follow-up, and continuity of care at the patient's place of residence. The MDT for patients with MDS includes a physical and rehabilitation medicine physician, hematologist, clinical psychologist, exercise therapy instructor;, occupational therapist, nurse, the patient's relatives, and the patient themselves. Based on the diagnosis of impairments in body structures and functions, activity limitations and participation restrictions, as well as the assessment of environmental and personal factors, a rehabilitation diagnosis is established, the rehabilitation potential is determined, and an individualized rehabilitation plan is developed based on short- and long-term rehabilitation goals.

5. Prevention and Dispensary Observation

• All patients with MDS are recommended continuous lifelong follow-up by a hematologist [1,118].

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

Comments: the dispensary follow-up schedule is not standardized and is set individually by each physician for each patient depending on the MDS variant, patient age, and comorbid conditions.

6. Organization of Medical Care

Medical care, except for medical care provided as part of clinical trials, is organized and delivered in accordance with Federal Law No. 323-FZ dated November 21, 2011 (as amended on December 25, 2013) "On the Fundamentals of Health Protection of Citizens in the Russian Federation":

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

• 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;

• based on these clinical guidelines;

• 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 myelodysplastic syndrome (MDS) or myelodysplastic/myeloproliferative neoplasm (MDS/MPN) is detected or suspected, general practitioners, district general practitioners, family physicians, various medical specialists (cardiologists, gastroenterologists, surgeons, etc.), and mid-level medical personnel shall refer the patient in the established manner for consultation to an outpatient hematology/oncology care center, or to 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 it is impossible to perform diagnostic tests, 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 MDS or MDS/MPN is detected or suspected during the provision of emergency medical care, the patient shall be transferred or referred to medical organizations providing medical care to patients with hematological diseases to determine the management strategy and the need for additional specialized anti-tumor treatment methods.

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

In a medical organization providing medical care to patients with MDS or MDS/MPN, the medical examination and treatment strategy is determined by hematologists, involving other medical specialists if necessary, and with a medical board (consilium) convened when required. The decision of the medical board is documented in a protocol, signed by the participating physicians, and entered into the patient's medical records.

Indications for hospitalization in a 24-hour inpatient or day-care unit of a medical organization providing specialized, including high-tech, medical care in the profile of "oncology" are determined by a hematologist / medical board involving other medical specialists if necessary.

Indications for elective hospitalization

1. Examination for the purpose of verifying the diagnosis of MDS or MDS/MPN in a patient with suspected MDS or MDS/MPN, when outpatient examination is not feasible.

2. Diagnosis of MDS or MDS/MPN relapse, worsening of hematopoietic aplasia, or transformation into acute leukemia.

3. Administration of the next course of IST or chemotherapy in a 24-hour inpatient or day-care setting.

4. Performance of elective surgical interventions.

5. Performance of elective extracorporeal blood purification methods and renal replacement therapy.

6. Performance of a planned allo-HSCT.

7. Administration of blood component replacement therapy.

Indications for emergency hospitalization

Emergency conditions in patients with MDS or MDS/MPN, as well as in suspected MDS or MDS/MPN:

• febrile neutropenia and infectious complications during chemotherapy, IMM, or IST;

• hemorrhagic syndrome;

• thrombotic complications;

• need for emergency blood transfusion;

• for patients with MDS/MPN, hyperleukocytosis of 100 × 10⁹/L or more;

• other systemic disorders caused by the underlying disease or treatment-related complications.

Indications for hospital discharge

1. Recovery of peripheral blood counts (leukocytes > 1 × 10⁹/L, granulocytes > 0.5 × 10⁹/L, platelets > 30–50 × 10⁹/L, hemoglobin > 80 g/L) after the regular course of chemotherapy, IMM, or IST.

2. Normothermia for 3–5 days and absence of uncontrolled infectious complications.

3. Relief of hemorrhagic complications.

4. Relief of thrombotic complications.

5. Resolution of systemic disorders caused by the underlying disease or treatment-related complications.

The conclusion regarding the feasibility of transferring the patient to a specialized medical organization is made after a prior consultation based on the provided medical documents and/or a preliminary examination of the patient by medical specialists of the medical organization to which the transfer is planned.

7. Additional Information

7.1. Disease-related factors (prognostic scoring systems are presented in Appendix G1)

Risk assessment based on MDS variant characteristics relies on prognostic scoring systems that combine individual clinical and hematological parameters. In 1997, under the auspices of the International Myelodysplasia Risk Analysis Workshop (IMRAW), P. Greenberg et al. developed the International Prognostic Scoring System (IPSS), which takes into account bone marrow blast percentage, cytogenetic abnormalities, and the severity of peripheral cytopenias (Table 1) [63].

The IPSS system has proven useful for predicting overall survival and the risk of transformation into acute myeloid leukemia (AML) in patients with MDS, thereby assisting in clinical decision-making [63].

Additional factors of prognostic significance, including multilineage dysplasia and severe transfusion-dependent anemia, were incorporated into the WHO Prognostic Scoring System (WPSS), which stratifies patients into 5 risk groups with distinct survival rates and probabilities of transformation into AML (Table 2). This scale allows for a more accurate prognosis in individual patients with MDS, particularly those in the IPSS low and intermediate-1 risk groups [64].

Relatively recently, the International Working Group for the Prognosis of Myelodysplastic Syndromes (IWG-PM), after analyzing long-term outcomes from a large multicenter study of treatment-naive patients with MDS, revised the IPSS system. The study analyzed the prognostic significance of a large number of even very rare karyotypic abnormalities, enabling their classification into 5 cytogenetic risk groups. Ultimately, the revised prognostic scoring system (IPSS-R) classifies the disease into 5 prognostic groups based on karyotype, blast cell count, and the severity of individual cytopenias (Table 3) [30].

The new IPSS-R prognostic system is more refined and improves patient stratification. Prognostic scoring can be technically simplified using an online calculator (http://advanced.ipss-r.com) or the free IPSS-R app for smartphones and tablets.

7.2. Other factors

Individual parameters characterizing the patient's somatic status can influence the natural course of the disease and therapeutic decisions. These include age, comorbidities, physical reserves, and the patient's nutritional and mental status.

When diagnosing MDS, an age over 60 years is an independent adverse prognostic factor. Age adjustment in assessing the probability of long-term survival has been provided for most prognostic systems. However, chronological age may differ from biological age, which must be considered when choosing therapeutic tactics.

A high frequency of comorbidities is common in older adults. One or more comorbidities are present at baseline in more than half of patients with MDS, significantly impacting survival. Heart diseases are the most frequent comorbidities determining the comorbidity status of MDS patients. Cardiovascular complications are most pronounced in patients with severe anemia and transfusion dependency.

Problems related to comorbidities manifest differently in low- and high-risk MDS patients. In low-risk MDS patients, comorbidities affect the prognosis by directly increasing the risk of death unrelated to transformation to AML. Conversely, in high-risk patients, the clinical significance of mild comorbidities is not as great compared to the poor prognosis of MDS itself. However, even in these patients, comorbidity affects treatment outcomes by limiting the choice of available therapeutic options.

To predict the impact of comorbidities on the final treatment outcomes in MDS patients, of greatest interest is the MDS-specific comorbidity index (MDS-CI), which requires assessing the functional status and/or the presence of heart, liver, kidney, and lung damage, as well as active or treated solid tumors (Appendix G3).

Based on the sum of points assigned to each indicator, the prognostic variant of the MDS-CI is determined: low (0), intermediate (1–2), and high (≥3 points). Subsequent application of the comorbidity index allows stratification of low- and intermediate-risk patients (but not high- and very-risk patients) into groups with different survival rates. Other things being equal, a high MDS-CI score both increases the risk of death from causes unrelated to transformation to AML (HR 2.46; p <0.001) and decreases overall survival rates (HR 2.09; p <0.001).

Thus, taking into account factors related to both the disease and the patient significantly improves the prognostic power of individual models, especially in low-risk groups [119].

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Khokhno A.V., Cand. Sci. (Med.), Head of the Clinical and Diagnostic Department of Hematology and Myeloid Neoplasms, Head of the Department of Diagnostics and Treatment of Hematological Diseases at the National Research Center for Hematology of the Russian Ministry of Health, Member of the National Hematological Society.

2. Baykov V.V., MD, PhD, Professor of the Department of Pathological Anatomy, Head of the Laboratory of Pathomorphology at the R.M. Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov First Saint Petersburg State Medical University of the Russian Ministry of Health, member of the Russian Society of Pathologists, member of the National Society of Oncohematology, member of the European Society of Pathology (ESP), member of the European Association for Haematopathology.

3. Gritsaev S.V., MD, PhD, hematologist at City Hospital No. 15, member of the National Hematology Society.

4. Dvirnyk V.N., PhD, Head of the Centralized Clinical Diagnostic Laboratory, National Research Center for Hematology of the Russian Ministry of Health, member of the National Hematology Society.

5. Dudina G.A., MD, PhD, Head of the Hematology Department, A.S. Loginov Moscow Clinical Scientific Center of the Moscow Healthcare Department, member of the National Hematology Society.

6. Kovrigina A.M., MD, PhD, Professor, Head of the Department of Pathology, National Research Center for Hematology of the Russian Ministry of Health, member of the Russian Society of Pathologists, member of the National Society of Oncohematology, member of the European Society of Pathology (ESP), member of the European Association for Haematopathology.

7. Konstantinova T.S., PhD, Head of the Regional Hematology Center, Sverdlovsk Regional Clinical Hospital No. 1, member of the National Hematology Society.

8. Kuzmina L.A., PhD, Head of the Department of Hemoblastosis Chemotherapy, Bone Marrow and Hematopoietic Stem Cell Transplantation, National Research Center for Hematology of the Russian Ministry of Health, member of the National Hematology Society.

9. Morozova E.V., MD, PhD, Head of the Department of Oncology, Hematology and Transplantation at the R.M. Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Associate Professor at the Department of Hematology, Transfusiology and Transplantology, Pavlov First Saint Petersburg State Medical University of the Russian Ministry of Health, member of the National Hematology Society.

10. Obukhova T.N., PhD, Head of the Laboratory of Karyology, National Research Center for Hematology of the Russian Ministry of Health, member of the National Hematology Society.

11. Parovichnikova E.N., MD, PhD, General Director of the National Research Center for Hematology of the Russian Ministry of Health, Chair of the National Hematology Society, expert of the European Working Group on Adult Acute Lymphoblastic Leukemia (EWGAALL).

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

13. Semochkin S.V., MD, PhD, Head of the High-Dose Chemotherapy and Bone Marrow Transplantation Group, National Medical Research Center for Radiology of the Russian Ministry of Health, Professor at the Department of Oncology, Hematology and Radiation Therapy, Pirogov Russian National Research Medical University of the Russian Ministry of Health, member of the National Hematology Society, member of the National Society of Pediatric Hematologists and Oncologists, member of the National Society of Oncologists and Hematologists, member of the EACR.

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

15. Shatokhin Yu.V., MD, PhD, Professor, Head of the Department of Hematology and Transfusiology at the Faculty of Advanced Training and Professional Retraining of Specialists, Rostov State Medical University, member of the National Hematology Society.

16. Shirin A.D., PhD, Senior Researcher, N.N. Blokhin Russian Cancer Research Center of the Russian Ministry of Health, member of the National Hematology Society, member of the National Society of Oncologists and Hematologists.

Healthcare Organization Section:

1. Gevorkyan Tigran Gagikovich, Deputy Director of the Research Institute of Clinical and Experimental Radiology, N.N. Blokhin National Medical Research Center of Oncology, Chief Oncologist of the Moscow Region.

2. Ivanov Sergey Anatolyevich, MD, PhD, Professor of the RAS, Director of the A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Center for Radiology of the Russian Ministry of Health.

3. Nevolskikh, Alexey A., Dr. of Sci. (Med.), Deputy Director for Clinical Work at the A.F. Tsyb MRRC – a branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

4. Khaylova Zhanna Vladimirovna, PhD, Deputy Director for Organizational and Methodological Work, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Center for Radiology of the Russian Ministry of Health.

   Conflict of interest: the authors declare no conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

• hematologists;

• oncologists;

• general practitioners (internal medicine);

• anesthesiologists-intensivists;

• clinical pharmacologists.

Rating scheme for the level of evidence certainty

Scale for assessing levels of reliability of evidence (LRE) for diagnostic methods (diagnostic interventions)

Grading system for levels of evidence for prevention, treatment and rehabilitation methods (preventive, therapeutic, rehabilitation interventions)

Grading system for the levels of evidentiary certainty (LEC) of recommendations for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Methodology for validation of guidelines

Methods for guideline validation:

1. external expert review;

2. internal expert review.

Description of the guideline validation methodology

The preliminary version of these recommendations was reviewed by independent experts who were asked to comment on the quality of evidence interpretation and guideline development. An expert review of the presentation of the recommendations and their readability was also carried out.

The draft version of the guidelines was presented and discussed at the meeting of the Hematology Expert Council and scientific conferences of the National Hematology Society.

The guidelines were discussed and approved by leading specialists from relevant federal centers of the Russian Federation and practicing physicians.

Final version

For the final version and quality control, the guidelines were re-analyzed by the members of the authoring team, who concluded that all significant comments and feedback from experts had been taken into account, and the risk of bias during development was minimized.

The latest changes and the final version of these guidelines were reviewed and approved at the meeting of the multidisciplinary Hematology Expert Council in April 2018.

Procedure for updating clinical guidelines

The clinical guideline update mechanism provides for their systematic updating—at least once every three years or upon the emergence of new information on the management of patients with this disease. 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, medical devices, and the results of clinical approbation.

Appendix A3. Reference Materials

Appendix A3.1. Induction and consolidation regimens

Maintenance treatment regimen options

Appendix A3.2. Recommendations for ESA administration

*-no increase in Hb level ≥10 g/L and/or reduction in transfusion dependence.

**- the G-CSF dose is adjusted individually to maintain the leukocyte count in the complete blood count at <10 x10⁹/L.

Appendix B. Physician Action Algorithms

General management algorithm for patients with suspected MDS or MDS/MPN

Management algorithm for low-risk MDS and MDS/MPN patients:

• IPSS low and intermediate-1 risk groups;

• IPSS-R very low, low, and intermediate risk groups;

• CPSS low and intermediate-1 risk groups

  

  
  

  Management algorithm for high-risk MDS and MDS/MPN patients:

• IPSS intermediate-2 and high risk groups;

• IPSS-R intermediate, high, and very high risk groups;

• CPSS intermediate-2 and high risk groups.

  

  
  

Appendix C. Patient Information

Myelodysplastic syndromes (MDS) are a group of diverse bone marrow (BM) disorders characterized by the inability of the BM to produce a sufficient number of healthy blood cells. MDS is often referred to as a "bone marrow failure disease." MDS primarily affects elderly individuals (the majority of patients are over 65 years of age), although this condition can also be diagnosed in individuals under 40.

The main features of MDS include cytopenia—a decrease in the count of red blood cells and hemoglobin, white blood cells, and platelets. In addition to low blood cell counts, mature blood cells circulating in the bloodstream may function improperly due to so-called dysplasia. Although MDS is not a syndrome but a disease—and even a group of diseases—the term "syndrome" remains in use.

The main types of cytopenias are:

1. Anemia is a decreased red blood cell count per 1 µL of blood, though hemoglobin parameters are more commonly used: patients with anemia present with pale skin, weakness, increased fatigue, drowsiness, dizziness, palpitations, and shortness of breath, both at rest and upon physical exertion. Each patient has a unique threshold hemoglobin level at which these symptoms begin to appear and worsen, prompting them to seek medical attention and helping to monitor the patient's condition over time.

2. Leukopenia is a low white blood cell count per 1 µL of blood. Decreased leukocyte and neutrophil counts, as well as impaired function, do not affect the patients' general well-being, but lead to an increased frequency of infectious complications.

3. Thrombocytopenia is a low platelet count per 1 µL of blood; patients with thrombocytopenia frequently exhibit hemorrhagic syndrome (appearance of red spots/hemorrhages on the skin and mucous membranes, gum bleeding—most often during oral hygiene procedures—nosebleeds, gastrointestinal bleeding, etc.). Given the impaired platelet function, these manifestations can occur at platelet levels >20×10⁹/L, but they are more commonly seen at levels below 20×10⁹/L.

Diagnosing MDS requires a blood test, a BM examination with karyotype analysis (to determine whether chromosomal abnormalities are present), and a complete medical evaluation. This helps the physician confirm or rule out MDS, identify any comorbid conditions, and choose further therapeutic tactics.

Currently, there are many treatment methods for MDS. The choice depends on the MDS subtype, hematopoiesis characteristics, risk group, patient age, presence and severity of comorbidities, and the availability of an HLA-matched donor.

The decision to initiate a specific therapy, particularly allogeneic hematopoietic stem cell transplantation (bone marrow transplantation), is made by the physician in consultation with the patient and their family.

Patient compliance with medical prescriptions and timely adherence to all established rules ensure the achievement of the best possible outcome.

All patients with MDS are advised to follow the hematologist's treatment instructions and avoid self-medication, limit sun exposure, saunas/baths, and physical therapy procedures. If harmful working conditions are present, a job change is recommended. Harmful working conditions include: work involving heavy physical and significant neuro-psychic strain, exposure to toxic agents, vibration, working at heights, operating moving machinery, driving vehicles, dispatching professions, etc.

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

Appendix G1. MDS prognostic scoring systems

To determine risk in MDS patients and select therapeutic strategies, prognostic scoring systems combining specific clinical and hematological parameters are used. Below are 3 prognostic scales: IPSS, IPSS-R, and WPSS.

IPSS Prognostic Scoring System

Original name: International prognostic scoring system for myelodysplastic syndromes (IPSS) [63]

Source: Greenberg P. et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. // Blood. 1997. Vol. 89, № 6. P. 2079–2088.

Type: rating scale

Purpose: clinical assessment of disease prognosis

Content and interpretation:

Notes:

Cytopenia: Hb <100 g/L; absolute neutrophil count <1.5×10⁹/L; platelets <100×10⁹/L.

Karyotype: good – normal karyotype, –Y, –20, –5; poor – chromosome 7 abnormalities and complex aberrations (≥3 chromosomes); intermediate – all other abnormalities.

IPSS-R Prognostic Scoring System

Original name: Revised international prognostic scoring system for myelodysplastic syndromes [30]

Source: Greenberg P.L. et al. Revised international prognostic scoring system for myelodysplastic syndromes // Blood. 2012. Vol. 120, № 12. P. 2454–2465.

Type: rating scale

Purpose: clinical assessment of disease prognosis

Content and interpretation:

WPSS Prognostic Scoring System

Original name: WHO classification-based Prognostic Scoring System (WPSS) [64]

Source: Malcovati L. et al. Impact of the degree of anemia on the outcome of patients with myelodysplastic syndrome and its integration into the WHO classification-based Prognostic Scoring System (WPSS). // Haematologica. 2011. Vol. 96, № 10. P. 1433–1440.

Type: rating scale

Purpose: clinical assessment of disease prognosis

Content and interpretation:

Notes:

1. WHO morphological variants: RA – refractory anemia; RARS – refractory anemia with ring sideroblasts; 5q– syndrome – MDS with isolated 5q deletion; RCMD – refractory cytopenia with multilineage dysplasia; RAEB-1 – refractory anemia with excess blasts 1, and RAEB-2 – refractory anemia with excess blasts 2.

2. Karyotype: good – normal, –Y, del(5q), del(20q); poor – complex abnormalities of ≥3 aberrations and any chromosome 7 anomalies; intermediate – all other karyotypic abnormalities.

3. Transfusion dependence (regular) is defined as at least one red blood cell transfusion every 8 weeks over a 4-month period [5]

Prognosis scoring systems in CMML

Chronic Myelomonocytic Leukemia Prognostic Scoring System (CPSS)

Original name: CMML-specific prognostic scoring system (CPSS) [150]

Source: Such E., et al. Development and validation of a prognostic scoring system for patients with chronic myelomonocytic leukemia. Blood. 2013;121:3005–3015.

Type: rating scale

Purpose: clinical assessment of disease prognosis

Content and interpretation:

*-Cytogenetic risk: low – normal karyotype, -Y; intermediate – all other aberrations (incl. del(20q), del(5q)); poor – +8, -7/del(7q), complex karyotype.

**- RBC transfusions of at least 1 unit every 8 weeks for 4 months.

Chronic myelomonocytic leukemia-specific prognostic scoring system incorporating molecular markers, CPSS-mol. [151]

Original name: prognostic scoring system for patients with chronic myelomonocytic leukemia. [150] prognostic score values of the CPSS-Mol

Source: Elena C., et al. Integrating clinical features and genetic lesions in the risk

assessment of patients with chronic myelomonocytic leukemia.  Blood. 2016;128:1408–1417.

Type: rating scale

Purpose: clinical assessment of disease prognosis

Content and interpretation:

*Cytogenetic risk: low – normal karyotype, -Y; intermediate – all other aberrations (incl. del(20q), del(5q)); poor – +8, -7/del(7q), complex karyotype.

** Molecular-genetic risk: low – no mutations in ASXL1, NRAS, RUNX1, SETBP1 genes; intermediate – mutations in ASXL1, NRAS, SETBP1 genes; high – mutations in the RUNX1 gene.

***Red blood cell suspension transfusions of at least 1 unit every 8 weeks for 4 months.

Appendix G2. Evaluation of treatment response in MDS and MDS/MPN

The efficacy of MDS therapy should be evaluated according to the International Working Group (IWG 2006) response criteria [3].

Original name: International Working Group (IWG) response criteria in myelodysplasia [65]

Type: other – response evaluation criteria

Purpose: evaluation of MDS therapy efficacy

Content and interpretation:

Evaluation of therapy efficacy (IWG 2006) [3]

Appendix G3. Comorbidity index for patients with MDS

To predict the impact of comorbidities on treatment outcomes in patients with MDS, the patient's comorbidity should be assessed using the MDS-specific comorbidity index (MDS-CI) [119].

Original name: MDS comorbidity index

Type: rating scale

Purpose: clinical evaluation of comorbidity

Content and interpretation:

MDS Comorbidity Index (MDS-CI)

Based on the sum of points assigned to each indicator, the prognostic variant of the MDS-CI is determined: low (0), intermediate (1–2), and high (≥3 points). Subsequent application of the comorbidity index allows stratification of low- and intermediate-risk patients (but not high- and very-risk patients) into groups with different survival rates. Other things being equal, a high MDS-CI score both increases the risk of death from causes unrelated to transformation to AML (HR 2.46; p <0.001) and decreases overall survival rates (HR 2.09; p <0.001).

Appendix G4. Comorbidity index for patients scheduled for allogeneic hematopoietic stem cell transplantation

In patients scheduled for hematopoietic stem cell transplantation (bone marrow transplantation), patient comorbidity must be assessed using the hematopoietic cell transplantation comorbidity index (HCT-CI) [105].

Original title: Hematopoietic cell transplantation comorbidity index

Type: rating scale

Purpose: clinical evaluation of comorbidity

Content and interpretation:

Comorbidity index for patients scheduled for hematopoietic stem cell transplantation (bone marrow transplantation) (HSC-CI) [105]