Ph-negative Myeloproliferative Neoplasms: Clinical Guidelines

List of Abbreviations

ADP - adenosine diphosphate

allo-HSCT – allogeneic hematopoietic stem cell transplantation

ALT - alanine aminotransferase

AST - aspartate aminotransferase

Auto-HSCT – autologous hematopoietic stem cell transplantation

aPTT - activated partial thromboplastin time

BC – blast crisis

WHO – World Health Organization

VTE - venous thromboembolism

CI – confidence interval

IFN — interferons (ATC L03AB)

PV – polycythemia vera

LDH – lactate dehydrogenase

MDS — myelodysplastic syndrome

MPN – myeloproliferative neoplasm

MRI – magnetic resonance imaging

MF – myelofibrosis

INR – international normalized ratio

LMWH — low-molecular-weight heparin (ATC B01AB Heparin group)

CVA – cerebrovascular accident

NSAIDs — non-steroidal anti-inflammatory and antirheumatic products (ATC M01A)

OS – overall survival

AML – acute myeloid leukemia

HR – hazard ratio

PMF – primary myelofibrosis

Post-PV MF – post-polycythemia vera myelofibrosis

Post-ET MF – post-essential thrombocythemia myelofibrosis

PCR – polymerase chain reaction

PEG — polyethylene glycol

ESR – erythrocyte sedimentation rate

SE – splenectomy

LoE – level of evidence

US – ultrasound examination

LER — level of evidence and recommendation

CML – chronic myeloid leukemia

ECG – electrocardiogram

EGD - esophagogastroduodenoscopy

ET – essential thrombocythemia

Echo-CG – echocardiography

CALR – calreticulin

DIPSS (Dynamic International Prognostic Scoring System) – Dynamic International Prognostic Scoring System

ECOG – Eastern Cooperative Oncology Group

ELN (European LeukemiaNet) – European LeukemiaNet

FISH (Fluorescence In Situ Hybridization) — fluorescence in situ hybridization

IPSET-thrombosis (The International Prognostic Score for ET) – International Prognostic Score for Thrombosis in Essential Thrombocythemia

IPSS (International Prognostic Scoring System) – International Prognostic Scoring System

IWG-MRT (The International Working Group for Myeloproliferative Neoplasms Research and Treatment) - International Working Group for Myeloproliferative Neoplasms Research and Treatment

MIPSS (Mutation-Enhanced International Prognostic Scoring System) — Mutation-Enhanced International Prognostic Scoring System

MF – grade of bone marrow stromal reticulin/collagen fibrosis determined by histochemical staining of bone marrow trephine biopsy sections using silver impregnation

MYCEC-PM (The Myelofibrosis Secondary to PV and ET – Prognostic Model) is a prognostic model for secondary myelofibrosis

NGS (next generation sequencing)

TGF-β (Transforming Growth Factor β) — transforming growth factor β; VEGF (Vascular Endothelial Growth Factor) — vascular endothelial growth factor

Terms and Definitions

Myelofibrosis is a morphological term that characterizes fibrosis of the bone marrow stroma with the displacement of hematopoietic elements. It occurs in metastatic and lymphomatous bone marrow involvement, acute leukemias, myelodysplastic syndromes, MDS/MPN, BCR-ABL1+ chronic myeloid leukemia, and hairy cell leukemia. Among non-neoplastic conditions, bone marrow myelofibrosis may be found in infectious and autoimmune diseases, in the late stages of bone marrow necrosis of various etiologies due to fibrohistiocytic proliferation with the replacement of necrotic bone marrow by fibrous tissue, or it can be detected during repeat trephine biopsy from the same site of the ilium.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Primary myelofibrosis (PMF), polycythemia vera (PV), and essential thrombocythemia (ET) form a group of heterogeneous hematopoietic disorders collectively known as Ph-negative myeloproliferative neoplasms (MPNs) [1–5]. MPNs are clonal disorders originating at the hematopoietic stem cell level, characterized by the proliferation of one or more myeloid cell lineages in the bone marrow with signs of preserved terminal differentiation, accompanied by alterations in peripheral blood counts [1–6].

Polycythemia vera (PV) is a clonal MPN characterized by the proliferation of erythroid, granulocytic, and megakaryocytic lineages of myelopoiesis with predominant proliferation of the erythroid lineage (panmyelosis), an increased red blood cell count, elevated hemoglobin concentration, thrombocytosis, and leukocytosis in the blood (pancytois), with erythropoiesis independent of normal cytokine regulation mechanisms. Nearly all patients carry the V617F mutation in the JAK2 gene or another functionally similar mutation.

Essential thrombocythemia (ET) is a clonal MPN with uncontrolled megakaryocyte proliferation, characterized by an increased number of large and giant megakaryocytes in the bone marrow, peripheral blood thrombocytosis (>450×10⁹/L), and a high risk of thrombosis and/or hemorrhage.

Primary myelofibrosis (PMF) is a morphological term that characterizes fibrosis of the bone marrow stroma with the displacement of hematopoietic elements. Myelofibrosis is classified as primary (PMF) or secondary resulting from the progression/transformation of PV or ET. Primary myelofibrosis arises de novo and is characterized by clonal stem cell proliferation, aberrant cytokine expression, bone marrow fibrosis, hepatosplenomegaly due to extramedullary hematopoiesis, tumor intoxication symptoms, cachexia, leucoerythroblastosis (a condition characterized by leukocytosis, a left shift of the differential white blood cell count up to blast cells, and the appearance of erythroblasts in the blood), progression leading to acute myeloid leukemia, and low survival rates. Secondary myelofibrosis occurs during the progression/transformation of PV or ET.

Myeloproliferative neoplasm, unclassifiable (MPN-U). According to the 5th edition of the World Health Organization (WHO) classification of 2024 [6], this diagnosis should be used when clinical, laboratory, and histological (based on bone marrow trephine biopsy) features of an MPN are present that do not meet the criteria for any specific entity of classical Ph-negative MPNs. Most frequently, this category is used in early disease stages (manifestation) when there is a discrepancy between clinical, laboratory, and morphological data; at the stage of bone marrow stromal fibrosis/osteosclerosis when myelodysplastic syndromes or disorders from the MDS/MPN category with stromal fibrosis are excluded; in the acceleration phase (10–19% blast cells in the bone marrow or blood); during a blast crisis (BC) of a previously diagnosed MPN; or in cases where an MPN coexists with inflammatory, metabolic, or neoplastic diseases that mask the primary features of a specific nosological entity. MPN-U is not diagnosed in the presence of an inadequate bone marrow trephine biopsy specimen size, a lack of anamnestic, clinical, or laboratory data provided by physicians, prior therapy with cytostatic agents or colony-stimulating factors, the presence of PDGFRA, PDGFRB, FGFR1 gene rearrangements, or the detection of the BCR::ABL1 chimeric gene [6].

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

The etiology of MPNs remains undetermined. The leading hypothesis is a multistep pathogenesis in which disease predisposition is realized under the influence of external factors that damage the genome of a normal cell, leading to the emergence of a clone with the accumulation of subsequent genetic events, accompanied by clonal evolution [5, 6].

Mutations in the JAK2 gene occur at the level of hematopoietic stem cells (progenitor cells) [7]. A mutation in exon 14 of the JAK2 gene (JAK2 V617F) is detected in more than 90% of patients with PV and in 60% of patients with ET or MF [8, 9]. Mutations in exon 12 of the JAK2 gene have been described in 2–3% of patients with PV, with erythroid lineage proliferation being the predominant morphological feature [10].

Mutations in the gene encoding the thrombopoietin receptor (MPL W515L/K) are observed in approximately 5–8% of all patients with MF and 1–4% of patients with ET [11].

Mutations in exon 9 of the CALR gene are observed in approximately 20–35% of all patients with ET and MF, accounting to 60–80% of JAK2/MPL-negative ET and MF cases [11–13]. The most frequent mutation variants in the CALR gene are a 52-base pair deletion (type 1) and a 5-base pair insertion (type 2). It has been noted that type 1 CALR mutations are more common in patients with PMF, whereas type 2 CALR mutations are predominantly associated with ET [14].

Mutations in genes involved in signal transduction (CBL and LNK/SH2B3), chromatin modification (TET2, EZH2, IDH1/2, ASXL1, and DNM3TA), RNA splicing (SF3B1, SRSF2, and U2AF1), and tumor suppression (the TP53 gene) can also be detected in patients with MPNs [15].

The triple-negative variant, which implies the absence of mutations in the JAK2, CALR, and MPL genes, occurs in approximately 10% of patients with PMF and is associated with a poor prognosis [15].

PMF patients with mutations in the CALR gene have better overall survival (OS) rates compared to patients carrying JAK2 V617F or MPL W515L/K mutations. Median survival was significantly higher in patients with type 1 mutations than in those with type 2 [14]. The median OS was 18 years in patients with CALR gene mutations, 9 years in those with the JAK2 V617F mutation or the MPL W515L/K mutation, and 3 years in patients with triple-negative status [17]. In a multivariate analysis adjusted for age, CALR gene mutations retained their significance compared to the JAK2 V617F mutation (p = 0.019) or triple-negative status (p < 0.001). The 10-year cumulative incidence of progression to blast crisis was also lower (9%) in patients with CALR gene mutations compared to 19% in patients with the JAK2 V617F mutation, 17% in those with the MPL W515L/K mutation, and 34% in those with triple-negative disease [17]. PMF patients with MPL gene mutations exhibit a low hemoglobin level at diagnosis and a high risk of developing transfusion dependency [18].

Mutations in the ASXL1, EZH2, SRSF2, TP53, IDH1, IDH2, and U2AF1 genes are considered high molecular risk mutations and are associated with worse OS and blast crisis-free survival [19]. Mutations in the ASXL1, EZH2, SRSF2, U2AF1, and RAS genes determine the prognosis for OS, whereas mutations in the ASXL1, SRSF2, TET2, TP53, and IDH1/2 genes are predictors of blast crisis risk in PMF patients [18]. Median OS in patients with at least one mutation in prognostically significant genes (ASXL1, EZH2, SRSF2, IDH1, IDH2) compared to patients without mutations in any of these genes was 81 versus 148 months (p < 0.0001) [20]. However, isolated ASXL1 gene mutations retained their prognostic significance after adjusting for prognostic factors included in the IPSS, DIPSS, and DIPSS-plus scores. OS and leukemia-free survival are influenced by the number of detected mutations. The median OS was 3 years in patients with two or more high molecular risk mutations, compared to 7 and 12 years in patients with one mutation and without mutations, respectively. Leukemia-free survival was 7, 11, and 27 years, respectively [21].

In patients with post-PV and post-ET MF, the prognostic significance of mutations in ASXL1, EZH2, SRSF2, TP53, IDH1, IDH2, U2AF1 genes, with the exception of the SRSF2 gene mutation, has not been established [22].

PV with a JAK2 exon 12 mutation is characterized by a higher hemoglobin concentration, as well as a lower platelet and leukocyte count at the time of diagnosis compared to PV with the JAK2 V617F mutation. The risks of thrombotic complications, progression to post-PV MF, and leukemic transformation do not depend on the patient's molecular status. However, the number of fatal outcomes is significantly higher in patients with the JAK2 V617F mutation [23].

ET with CALR gene mutations is characterized by a younger age, male predominance, high platelet count, low hemoglobin concentration, lower leukocyte count, and a lower risk of thrombotic complications compared to ET with a JAK2 gene mutation. At the same time, the presence of mutations in the MPL gene may be associated with a high risk of transformation into post-ET MF. In ET patients with CALR gene mutations compared to those with MPL gene mutations, there is a low risk of thrombotic complications, with similar hemoglobin levels, leukocyte and platelet counts. Mutations in the CALR gene do not affect the risk of thrombotic complications, OS rates, disease progression with the development of post-ET MF, or leukemic transformation [24].

The widespread use of NGS (next-generation sequencing) has made it possible to identify adverse mutations in a number of genes in patients with PV and ET, which are associated with an increased risk of disease progression with the development of leukemic transformation [25]. In patients with PV, the presence of at least one mutation in the ASXL1, SRSF2, IDH2 genes was associated with worse OS and MF-free survival, but did not have a significant impact on leukemia-free survival rates [26]. In patients with ET, mutations in the SH2B3, IDH2, U2AF1, SF3B1, EZH2, TP53 genes were identified as significant prognostically unfavorable factors regarding OS, MF-free survival, and leukemic transformation. The development of post-ET MF was more frequently observed in patients with mutations in the SF3B1 and IDH1/2 genes, although a persistently high or stable increase in the JAK2 V617F allele burden during cytoreductive therapy was the most significant predictor of progression to secondary MF [27].

1.3 Epidemiology of the Disease or Condition

A number of studies report an increase in the incidence of MPNs over the past decade, which is attributed not only to the continuous improvement of diagnostic and classification criteria for these diseases. However, many studies are based on data obtained before 2008 and rely on earlier approaches to the diagnosis of MPNs [28, 29].

The overall standardized incidence rate of major Ph-negative MPNs in Sweden was 4.45 (4.34 – 4.56), PV – 1.48 (1.42 – 1.54), ET – 1.6 (1.53 – 1.66), PMF – 0.52 (0.48 – 0.56); in Australia – 2.3 (2.25 – 2.35), PV – 0.90 (0.87 – 0.94), ET – 0.95 (0.92 – 0.98), PMF – 0.45 (0.42 – 0.47); in Canada – 2.72 (2.63 – 2.78), PV – 0.44 (0.41 – 0.47), ET – 1.16 (1.11 – 1.21), PMF – 0.8 (0.76 – 0.84); in Belarus – 1.96 (1.86 – 2.07), PV – 0.93 (0.86 – 1.01), ET – 0.63 (0.57 – 0.70), PMF – 0.40 (0.36 – 0.45) per 100,000 population [29–33]. Crude incidence rates in Saint Petersburg for PV were 0.83 (0.50 – 1.15), ET – 1.00 (0.60 – 2.10), PMF – 1.01 (0.65 – 1.35) [33].

The presented differences in incidence are most likely related to deficiencies in primary diagnostics and the lack of a unified registration system, rather than differing disease prevalence.

1.4 Features of Coding the Disease or Condition

D45 Polycythemia vera

D47.1 Chronic myeloproliferative disease

D47.3 Essential (hemorrhagic) thrombocythemia

D47.4 Myelofibrosis

D75.1 Secondary polycythemia

1.5 Classification of the disease or condition

In accordance with the 5th edition of the WHO classification (2024), the MPN group comprises eight nosologically defined disease forms:

1) chronic myeloid leukemia, BCR::ABL1+;

2) chronic neutrophilic leukemia;

3) polycythemia vera;

4) essential thrombocythemia;

5) primary myelofibrosis (prefibrotic stage and overt/fibrotic stage);

6) chronic eosinophilic leukemia;

7) juvenile myelomonocytic leukemia;

8) MPN, unclassifiable [6].

1.6 Clinical presentation of the disease or condition

Clinical presentation of polycythemia vera

PV is characterized by the presence of two main syndromes: plethoric and myeloproliferative.

Plethoric syndrome (from "plethora" – fullness of blood) is characterized by an increase in circulating red blood cell mass, which leads to complaints of dizziness, headaches, visual impairment, pruritus, and angina attacks. Upon examination, the skin and visible mucous membranes have a red-cyanotic hue. Cooperman's sign is positive: the color of the soft palate is altered while the normal coloration of the hard palate is preserved. Vascular complications include arterial and venous thrombosis of any localization. Microvascular complications include "scintillating scotomas" (spots before the eyes), transient ischemic attack, and erythromelalgia (episodes of redness of the fingers and toes accompanied by pain and burning).

Myeloproliferative syndrome is caused by the hyperplasia of three hematopoietic lineages. It manifests as pruritus, sweating, weakness, elevated body temperature, and bone pain. Increased granulocyte turnover is accompanied by impaired urate metabolism, which manifests as uric acid diathesis, kidney stone formation, gout, and gouty polyarthralgia. Splenomegaly (less commonly, hepatomegaly) may be caused by an increase in the sequestering function of the spleen. Panctyosis in the blood is characteristic [37].

Clinical presentation of essential thrombocythemia

Patients with ET may experience general symptoms: fatigue, decreased concentration. Microcirculatory complications manifest as painful redness in the fingers and toes, swelling, and burning (erythromelalgia). Cerebral microcirculation disorders (transient ischemic attacks) represent periodic temporary disturbances of vision, speech (dysarthria), or gait, headache, impaired mental clarity, dizziness, or migraine. Thromboembolism is the most common and dangerous complication in ET, manifested by thrombosis of the venous and arterial systems, in particular, large abdominal vessels (portal vein and its branches, splenic and mesenteric veins), lower extremity veins, coronary arteries, and cerebral arteries. Hemorrhagic complications include bleeding. During pregnancy, there is an increased frequency of spontaneous pregnancy losses, placental infarctions followed by impaired growth and fetal death [1, 2, 3, 35–37].

Clinical presentation of primary myelofibrosis

Phases of PMF

The clinical course of PMF distinguishes phases that reflect the degree of disease progression: chronic phase, accelerated phase, terminal phase of blastic transformation, or blast crisis. The chronic phase is the initial stage of PMF and is diagnosed in the majority (>90%) of newly diagnosed patients. The most characteristic signs are changes in the complete blood count (leukoerythroblastosis, gradual shift in the neutrophil and erythroid series toward immature forms with the presence of intermediate maturation stages), enlargement of the liver and spleen, and the presence of symptoms of tumor intoxication (fever, weight loss, profuse night sweats). The accelerated phase is diagnosed in the presence of 10–19% blasts in the bone marrow or peripheral blood [84]. Blast crisis is the terminal stage of the pathological process in PMF. The diagnostic criterion for blast crisis in PMF is the presence of at least 20% blast cells in the peripheral blood or bone marrow [84].

Stages of PMF

The 5th edition of the WHO classification (2024) distinguishes prefibrotic/early and overt/fibrotic stages of PMF. Differential diagnosis should be based on bone marrow trephine biopsy histology, laboratory characteristics, and clinical data. The prefibrotic stage is characterized by bone marrow hypercellularity with expansion of the granulocytic lineage, proliferation of the megakaryocytic lineage with atypia, disruption of histotopography and megakaryocyte structure, and the absence or minimal reticulin fibrosis (MF-0/MF-1 according to the European grading system). The prefibrotic stage of PMF meets the main criteria of the WHO classification, but leukoerythroblastosis, splenomegaly, and anemia are most often absent. In clinical practice, the appearance of anemia, an elevated leukocyte count, or an increased serum LDH concentration should alert the physician and prompt a review of the diagnosis. The fibrotic stage is morphologically characterized by reticulin and collagen bone marrow fibrosis (MF-2/MF-3 according to the European grading system), reduction of the erythroid lineage, and pronounced atypia of megakaryopoiesis elements. The clinical picture is characterized by splenomegaly, anemia, elevated LDH activity, leukoerythroblastosis in the hemogram, and the appearance of teardrop-shaped erythrocytes (dacrocytes) [85].

Clinical presentation

The clinical presentation of PMF is characterized by a wide variety of manifestations. For a number of years, the initial period of the disease may remain asymptomatic in the majority of patients. The disease is frequently discovered unexpectedly during a complete blood count as part of a routine check-up or regarding a comorbid condition. The clinical manifestations of PMF are not pathognomonic and consist of several syndromes [1, 2, 3, 35–37]:

tumor intoxication syndrome — progressive weakness not corresponding to the degree of anemia, decreased appetite, weight loss, sweating, low-grade fever, bone and joint pain, skin pruritus, worsening of comorbid conditions;

tumor proliferation syndrome — pain and a feeling of heaviness in the left upper quadrant due to splenomegaly, hepatomegaly. With a prolonged course of the disease, patients may also develop foci of extramedullary hematopoiesis in other organs and tissues (lymph nodes, lungs, pleura, peritoneum, spinal and brain, skin, soft tissues of the extremities), causing clinical manifestations associated with the involvement of these organs;

anemic syndrome — generalized weakness, dyspnea, decreased exercise tolerance, pallor of the skin and mucous membranes, tachycardia, arterial hypotension, worsening of cardiovascular diseases;

thrombotic complications — thrombosis and thromboembolism of vessels in various organs and tissues, peripheral thrombophlebitis, myocardial infarction, cerebrovascular accidents, which serve as the reason for examination in cases of asymptomatic PMF;

• infectious complication syndrome — development of opportunistic infections or a more severe course of common infectious diseases;

• hemorrhagic syndrome — bleeding from minimal trauma or spontaneous petechial or ecchymotic hemorrhages. The cause of bleeding may be thrombocytopenia against the background of bone marrow fibrosis, hyperthrombocytosis, and secondary von Willebrand factor deficiency, coagulopathy due to liver dysfunction and the development of portal hypertension;

• clinical manifestations caused by organ compression due to pronounced splenomegaly, hepatomegaly;

• portal hypertension (the following causes of hepatic blocks are distinguished: presinusoidal thrombotic block, sinusoidal obstruction, postsinusoidal block of the Budd–Chiari syndrome type).

Transformation of polycythemia vera and essential thrombocythemia into myelofibrosis

Clinically, the transformation of PV and ET into MF is manifested by a decrease in the number of blood cellular elements (anemia is frequently observed), the appearance of a left shift in the granulocytic lineage and erythrokaryocytes in the hemogram, and splenomegaly due to the emergence of extramedullary myelopoiesis. Morphologically, there is a similarity between post-PV MF and PMF. Distinctive features of post-PV MF include the rarity of dense megakaryocyte clusters, the absence of bizarre hyperchromic/atypical forms, and nuclear hypersegmentation of predominantly sparsely distributed megakaryocytes among the reticulin and collagen stroma. Cells with nuclear-cytoplasmic ratio abnormalities featuring large hyperchromic hypolobular nuclei (with immature morphology) are few in number [82].

Progression/transformation of PV should include:

• appearance of MDS-like morphological features (transformation into MDS is possible);

• appearance of neutrophilia (of the chronic neutrophilic leukemia type);

• appearance of marked monocytosis and MDS/MPN-like features (of the chronic myelomonocytic leukemia type) [82].

Prognosis

In general, the prognosis for patients with PV is favorable and depends on the nature and severity of thrombotic complications, the time to transformation into post-polycythemia vera myelofibrosis (post-PV MF) or disease progression resulting in blast phase / acute myeloid leukemia (AML). According to WHO data, the 10-year survival rate for patients with PV exceeds 75%. The risk of transformation to AML is 5%, and the risk of developing myelofibrosis is less than 10% [6]. Causes of death in patients with PV may include thrombosis, hemorrhagic and infectious complications, and internal organ dysfunction, the frequency of which increases significantly upon the development of post-PV MF or transformation to AML [39].

Risk stratification of thrombotic complications in PV

Risk stratification in patients with PV is primarily intended to assess the probability of thrombotic complications, which contribute the most to mortality and disability. Age over 60 years, history of thrombosis, cardiovascular risk factors (smoking, arterial hypertension, diabetes mellitus, dyslipidemia, overweight, physical inactivity) are the main criteria for classifying PV patients into low-risk (0 risk factors), intermediate-risk (1 risk factor — cardiovascular risk factors), or high-risk (1–2 risk factors — age over 60 years and/or history of thrombosis regardless of the presence of cardiovascular risk factors) groups [40].

Hyperthrombocytosis (>1000×10⁹/L) is a risk factor for hemorrhagic complications due to the development of acquired von Willebrand syndrome [41].

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for establishing the diagnosis/condition: based on:

1) anamnestic data,

2) physical examination,

3) laboratory studies,

4) instrumental examination, etc.

Comments:

Major criteria:

· hemoglobin level greater than 165 g/L in men and 160 g/L in women, or hematocrit greater than 49% in men and greater than 48% in women, or an increase in red blood cell mass greater than 25% of calculated values;

· hypercellular bone marrow due to the expansion of three myelopoiesis lineages, including expansion of the erythroid lineage, granulocytic lineage, and proliferation of megakaryocytes represented by pleomorphic and mature forms;

· JAK2 gene mutation in exon 14 (JAK2 V617F) or exon 12

Minor criterion:

· blood erythropoietin (EPO) level below reference values.

The diagnosis of PV is established in the presence of all three major criteria or the first two major and the minor criterion.

Comments:

Major criteria:

· platelet count greater than 450×10⁹/L;

· proliferation of the megakaryocytic lineage with an increase in the number of large and giant megakaryocytes with hyperlobular nuclei; absence of significant expansion or rejuvenation of neutrophil granulopoiesis; very rarely — a minor increase in the degree of reticulin fibrosis;

· failure to meet WHO criteria for BCR::ABL1-positive chronic myeloid leukemia, polycythemia vera, primary myelofibrosis, or other myeloid neoplasms;

· presence of JAK2V617F, CALR, or MPL mutation.

Minor criterion:

· in the absence of JAK2, CALR, or MPL mutation, presence of a clonal marker or absence of evidence for reactive thrombocytosis.

The diagnosis is definite in the presence of all four major criteria or the first three major and the minor criterion.

Comments:

Criteria for establishing the prefibrotic and fibrotic stages of PMF differ.

Prefibrotic stage of PMF

Major criteria:

· Megakaryocyte proliferation with atypia¹ without reticulin fibrosis greater than grade 1 (MF-0 or MF-1), accompanied by increased bone marrow cellularity, proliferation of the granulocytic lineage, and often decreased erythropoiesis.

· Failure to meet WHO criteria for the diagnosis of CML, PV, ET, MDS, or other myeloproliferative neoplasms².

· Detection of mutations in JAK2, CALR, or MPL; in the absence of these mutations, the presence of other clonal markers (ASXL1, EZH2, TET2, IDH1/2, SRSF2, SF3B1), or the absence of low-grade reticulin fibrosis (MF-1 grade) of reactive nature (infections, autoimmune diseases, chronic inflammatory conditions, hairy cell leukemia or other lymphoproliferative neoplasms, tumor metastases, or chronic intoxications)³.

Minor criteria:

a) anemia not associated with comorbid conditions;

b) leukocytosis ≥11×10⁹/L;

c) enlargement of spleen size determined by palpation and/or visualization;

d) elevated LDH activity above normal.

To establish the diagnosis of "prefibrotic stage of PMF", the presence of all three major criteria and at least one minor criterion, confirmed in two consecutive determinations, is required.

Comments:

Mandatory criteria:

· initially diagnosed ET or PV according to WHO criteria;

· bone marrow fibrosis MF-2–3 according to the European grading system.

Additional criteria:

· anemia or a decrease in hemoglobin concentration ≥20 g/L from baseline;

·peripheral blood leukocytosis and erythroblastosis;

· splenomegaly (spleen extending >5 cm below the left costal margin);

· elevated serum LDH activity;

· presence of constitutional symptoms.

Establishing a diagnosis of post-PV MF or post-ET MF requires the presence of two obligatory criteria and at least two minor criteria.

________________________________________________________________________

¹Small to large megakaryocytes with immature morphology—abnormal nuclear-cytoplasmic ratio, atypical hyperchromatic hypolobulated/bizarre nuclei, forming loose and dense clusters.

² Exclusion of PV is based on hemoglobin and hematocrit levels. Measurement of red cell mass is not required. BCR-ABL1 is absent. No dyserythropoiesis or dysgranulopoiesis.

³Patients with conditions leading to reactive myelofibrosis.

Fibrotic stage of PMF

Major criteria:

·megakaryocyte proliferation with atypia accompanied by grade 2 or 3 reticulin and/or collagen fibrosis (MF-2 or MF-3);

· failure to meet WHO criteria for ET, PV, CML, MDS, or other myeloid neoplasms;

· detection of JAK2, CALR, or MPL mutations, or in the absence of these mutations, presence of other clonal markers (ASXL1, EZH2, TET2, IDH1/2, SRSF2, SF3B1) or absence of low-grade reactive reticulin fibrosis (grade MF-1) (due to infections, autoimmune disorders, chronic inflammatory conditions, hairy cell leukemia or other lymphoproliferative neoplasms, tumor metastases, or chronic intoxications).

Minor criteria:

a) anemia not associated with comorbid conditions;

b) leukocytosis ≥11×10⁹/L;

c) enlargement of spleen size determined by palpation and/or visualization;

c) elevated serum LDH activity above normal limits;

d) leukoerythroblastosis.

Verification of the diagnosis of the fibrotic stage of PMF requires the presence of all three major criteria and at least one minor criterion confirmed in two consecutive determinations.

Comments:

Major criteria:

·ET or PV primarily diagnosed according to WHO criteria;

· Bone marrow fibrosis MF-2 or MF-3 (0–3 scale) or 3–4 (0–4 scale).

Minor criteria:

a) anemia or a decrease in hemoglobin level by more than 20 g/L;

b) leukoerythroblastosis;

c) splenomegaly (palpable spleen greater than 5 cm from the costal margin) or development of splenomegaly;

c) elevated serum LDH activity above normal limits;

d) symptoms of tumor intoxication: loss of more than 10% of body weight over 6 months, night sweats, unexplained fever (>37.5 °C).

The diagnosis of post-PV MF and post-ET MF can be established in the presence of two major and at least two minor criteria.

2.1 Complaints and Anamnesis

Comments:

Monitoring of symptoms and quality of life in patients with MPN should be performed using standardized questionnaires [133]. The MPN10 questionnaire is one of the simplest and most convenient instruments in clinical practice for assessing specific symptoms in patients with MPN and monitoring disease course [133-135]. The MPN10 questionnaire allows assessing the severity of 10 symptoms most frequently encountered in this category of patients: fatigue, early satiety, abdominal discomfort, lethargy (decreased activity), concentration problems, night sweats, pruritus, bone pain, fever, and unintentional weight loss. Symptoms are rated by the patient on a 10-point scale: 0 — no symptom, 10 — maximum imaginable severity of the symptom (Appendix G1). The maximum level of fatigue is assessed over the past 24 hours; the maximum levels of early satiety, abdominal discomfort, lethargy (decreased activity), concentration problems, night sweats, pruritus, bone pain, and fever — over the past week; the maximum level of unintentional weight loss — over the past 6 months. Processing of MPN10 questionnaire data involves, alongside the analysis of severity information for each of the 10 symptoms on a 10-point scale, the calculation of a total symptom score as the mean of their severity scores. The range of the total symptom score is from 0 to 100 points (higher scores indicate greater overall severity of all symptoms). The questionnaire should be used to assess clinical response to therapy. It should be administered prior to therapy initiation and regularly during treatment [133, 134]. Treatment response is defined as a reduction in the total MPN10 score by ≥50% [135]. Utilizing information obtained directly from the patient during the analysis of disease symptoms and the assessment of their dynamics during treatment contributes to the implementation of a patient-centered approach.

The questionnaire should be used to evaluate clinical response to therapy (Appendix G1).

2.2 Physical Examination

Comments: physical examination includes evaluation of the skin color and visible mucous membranes, examination of the skin of the lower extremities (pigmentation, trophic disorders, edema, hemorrhages), palpation of the liver and spleen, and assessment of the lungs, heart, gastrointestinal tract, and kidneys.

2.3 Laboratory Diagnostics

Comments: the test should be performed at the time of diagnosis, and subsequently at least once every three months or more frequently in accordance with platelet, leukocyte, and hemoglobin levels.

Comments: testing blood EPO levels is a minor diagnostic criterion in establishing the diagnosis of PV.

Comments: in MPN, particularly PMF, anemia can have a mixed origin (anemia of chronic disease and iron deficiency). Assessment of iron metabolism will allow determination of the leading cause of the anemia syndrome and prescription of pathogenetic therapy. During follow-up, iron metabolism testing should be performed upon the development of anemia, a decrease in hemoglobin by 20 g/L from the baseline level, or the appearance of clinical signs of tissue iron deficiency.

Comments: detection of the JAK2V617F mutation makes it highly probable to establish a diagnosis of PV in patients with a corresponding clinical presentation; detection of JAK2V617F, MPLW515L/K mutations, and CALR exon 9 mutations makes it highly probable to establish a diagnosis of PMF or ET in patients with a corresponding clinical presentation. Molecular genetic testing allows for differential diagnosis both within the MPN group and between MPNs and secondary erythrocytosis, thrombocytosis, and myelofibrosis. However, in 13-17% of MPN cases, driver mutations are not detected

Comments: patients with Ph-negative MPNs have a high risk of both thrombotic and hemorrhagic complications. A coagulogram (exploratory hemostasis assay) is performed at the time of diagnosis, and subsequently according to clinical indications.

Comments: serum LDH activity level is a minor diagnostic criterion for PMF. A routine general clinical blood chemistry panel is performed at the time of diagnosis, at least once every 6 months during follow-up, and at least once every three months during cytoreductive therapy.

Comments: mutations in exon 12 of the JAK2 gene (JAK2V617F) are detected in 2-5% of cases in PV.

Comments: the detection of mutations in the ASXL1, EZH2, TET2, IDH1/2, SRSF2, and SF3B1 genes in patients with Ph-negative MPNs in the absence of driver mutations confirms clonality and provides the basis for applying a major diagnostic criterion [9]. The presence of mutations in the ASXL1, EZH2, IDH1/2, and SRSF2 genes in patients with PMF determines a high risk of progression and short overall survival.

Comments: The detection rate of chromosomal aberrations is up to 10% at the time of diagnosis. The detection of chromosomal aberrations during standard cytogenetic testing is an unfavorable prognostic criterion when determining the risk category according to the DIPSS+ score (Appendix G). The management strategy for patients with MPNs is based on determining the prognostic risk group.

determination of antibodies to Treponema pallidum (Treponema pallidum) by enzyme-linked immunosorbent assay (ELISA) in blood, or determination of antibodies to Treponema pallidum (Treponema pallidum) in non-treponemal tests (RPR, VDRL) (qualitative and semi-quantitative assay) in blood serum;

HIV antibodies (determination of antibodies of classes M and G (IgM, IgG) to human immunodeficiency virus HIV-1 (Human immunodeficiency virus HIV 1) in blood; determination of antibodies of classes M and G (IgM, IgG) to human immunodeficiency virus HIV-2 (Human immunodeficiency virus HIV 2) in blood;

tests for viral hepatitis B and C — determination of hepatitis B virus (Hepatitis B virus) surface antigen (HBsAg) in blood and determination of hepatitis C virus (Hepatitis C virus) antigen in blood.

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

2.4 Instrumental Diagnostics

Comments: bone marrow histological examination at the time of diagnosis should be performed in all patients with borderline hemoglobin and hematocrit levels, which allows for the exclusion of ET and PMF. Bone marrow histological examination has been included in the major diagnostic criteria for PMF in the WHO classification.

During follow-up, the study is performed according to clinical indications (confirmation of disease progression or remission).

Comments: at the time of diagnosis, then at least once a year, and additionally as clinically indicated.

Comments: the study makes it possible to detect both direct and indirect signs of portal vascular thrombosis, establish a timely diagnosis, and determine management tactics. In cases of acute thrombosis, hospitalization in a hematology department is necessary.

Comments: acute surgical abdominal pathologies are extremely dangerous and require urgent surgical intervention. Portal system thrombosis is classified into complete and partial, as well as acute and chronic forms. The acute form can manifest with ischemia and intestinal infarction due to the spread of the thrombus to the mesenteric vessels. The chronic form is often asymptomatic due to the activation of compensatory mechanisms, such as dilation of the hepatic artery and the development of a collateral network. Manifestations of chronic thrombosis may include gastrointestinal bleeding as a consequence of portal hypertension and biliopathy. In such cases, surgical treatment should be considered (splenectomy, portacaval shunt creation, endoscopic variceal ligation of esophageal varices).

Comments: this category of patients has a high risk of bleeding from esophageal and gastric varices. In the absence of bleeding risk from esophageal varices, EGD is performed at least once a year. If there is a risk of bleeding from esophageal varices, the procedure is performed at least once every 3 months.

Comments: Identifying risk factors for cardiovascular disease in patients with MPN allows for the timely identification of patients who require active monitoring and prophylactic hemocorrective therapy in combination with specific cytoreductive therapy.

2.5 Other Procedures

Comments: according to research, the most robust risk factors for thrombotic complications in PV are age over 60 years and a history of thrombosis. It is also advisable to consider general risk factors for cardiovascular, thrombotic, and hemorrhagic complications (Appendix G2). To assess individual prognosis, it is advisable to use the index developed in 2013 (Appendix G3).

Comments: based on international multicenter studies, WHO experts developed the International Prognostic Score for ET (IPSET-thrombosis) (Appendix G4).

Comments: OS prognostication is based on the assessment of clinical, laboratory, as well as molecular characteristics. Adverse mutations are detected in 2% of PV patients. New data formed the basis for the development of the Mutation-Enhanced International Prognostic Score System for Polycythemia Vera (MIPSS-PV) (Appendix G).

Comments: in 2009, F. Cervantes et al. proposed the International Prognostic Scoring System (IPSS), which is used to determine prognosis at the time of diagnosis. The following factors were identified as significantly affecting patient survival: age, hemoglobin level, percentage of blasts in peripheral blood, and the presence of constitutional symptoms. The resulting prognostic system uses a scoring method where one point is assigned to each of the features (Appendix G5). Patient groups categorized by the number of prognostic scores differ statistically significantly in overall survival duration.

In 2010, the IPSS system was modified by F. Passamonti et al. by assigning two points instead of one to the hemoglobin level factor of less than 100 g/L. The risk group classification based on scores was also modified (Appendix G6). The new Dynamic IPSS (DIPSS) prognostic index is capable of predicting the risk of transformation at any point of evaluation, not just at diagnosis. Prognosis in PMF is influenced by a number of molecular markers — mutations in the JAK2, MPL, CALR, EZH2, ASXL1, IDH1/2, and SRSF2 genes. These markers are included in the Molecular and Clinical International Prognostic Systems (MIPSS)

Comments: prognostication of ET clinical course is based on a comprehensive assessment of clinical, laboratory, and molecular data. Adverse mutations are detected in 10% of ET cases. Studies have confirmed the independent prognostically adverse impact on survival rates of mutations in SF3B1/SRSF2 genes, age >60 years, and male sex. This information formed the basis of the International Prognostic System for ET incorporating Molecular and Genetic Mutations (MIPSS-ET)

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

3.1 Treatment of polycythemia vera

Goals of PV therapy: prevention and treatment of thrombotic complications; control of constitutional symptoms (weight loss, sweating, fever); minimization of the risks of leukemic transformation and post-PV myelofibrosis; prevention of complications during pregnancy and surgical procedures.

Comments: phlebotomy is performed under sterile conditions in a treatment room. Contraindications: shock, collapse, and other conditions accompanied by a drop in blood pressure, anemia, cachexia, pronounced cerebral arteriosclerosis, a history of thrombotic and hemorrhagic events, advanced age. The volume of blood removal depends on the patient's general condition and averages 250–500 ml, followed by replacement of the circulating blood volume with 0.9% sodium chloride solution** or with preliminary intravenous drip infusion of fluid exceeding the planned phlebotomy volume. To reduce the risk of thrombosis and treat it during hemexfusion, intravenous administration of 5,000 IU of heparin sodium** is possible, including adding it to the replacement fluid infusion. Phlebotomies are performed every other day, and in patients with concomitant cardiovascular and pulmonary pathology — twice a week (or the volume of blood removed during the procedure is reduced). The main goal of treatment is to maintain hematocrit within 40–45%. Hemoglobin concentration is not taken into account when deciding on phlebotomy sessions [46]. An alternative to phlebotomies is automated erythrocytapферез.

Comments: therapy with low doses of #acetylsalicylic acid** is effective for relieving vasomotor symptoms associated with PV. Vasomotor symptoms include headaches, dizziness, transient neurological disturbances, scotomas, tinnitus, atypical chest discomfort, paresthesias, and erythromelalgia. These symptoms are caused by abnormal platelet-endothelial interactions in the microvasculature. Histopathological studies in erythromelalgia have revealed platelet-rich arteriolar microthrombi with endothelial inflammation and vascular intima proliferation, accompanied by increased platelet consumption.

Comments: smoking cessation, blood pressure normalization, correction of hypercholesterolemia and hyperglycemia, weight normalization, and adequate treatment of cardiovascular diseases reduce the risk of thrombotic complications.

Comments: medications should be prescribed while monitoring blood uric acid levels in accordance with the instructions.

Comments: there is no pathogenetic treatment for pruritus (as a constitutional symptom of MPN). Symptomatic therapy is administered.

Comments: the choice of first-line drug is determined by age (prescribing #interferon alfa-2b** at 0.5–5 million IU subcutaneously 3–5 times a week, subcutaneous administration, long-term, preferably in young patients [53, 54, 59, 137, 138, 139]); comorbidities (#interferon alfa-2b** should be prescribed with caution in autoimmune diseases, epilepsy, depression; #hydroxycarbamide** should be prescribed with caution in basal cell carcinoma, cataract); #hydroxycarbamide** is contraindicated during pregnancy (except when the benefit outweighs the potential risk of the drug); #ruxolitinib** is approved for prescription in case of resistance or intolerance to #hydroxycarbamide**; prescription according to individual indications is possible in case of resistance or intolerance to #interferon alfa-2b** preparations, thrombotic and/or hemorrhagic complications, portal hypertension syndrome, Budd-Chiari syndrome (Appendix A3, Table 1) [77].

It is currently well established that #interferon alfa-2b** can control hematocrit levels, spleen size, and symptoms of tumor intoxication in the majority of PV patients. Therapy with #peginterferon alfa-2b** at a dosage of 0.5 mcg/kg (35 mcg/week) once weekly, administered subcutaneously, allows achieving hematologic remissions in 80% of cases, as well as a reduction in the JAK2V617F allele burden (complete molecular remission in 5–10%) [58, 60, 137, 138, 140]. However, the widespread use of interferons is limited by poor tolerability. Adverse effects were reported in 96% of patients, and 22% discontinued treatment due to adverse events.

In a phase 3 clinical trial, #ruxolitinib** demonstrated superiority over #hydroxycarbamide** in PV patients with intolerance or resistance to #hydroxycarbamide** [61, 76, 77]. Hematocrit control was 60% for #ruxolitinib** versus 20% for #hydroxycarbamide**. Control of spleen size and constitutional symptoms was superior with #ruxolitinib**.

#Busulfan** therapy is effective in PV patients. In 65 PV patients diagnosed before the age of 60 who received #busulfan**, the median survival was 19 years. Only 2 patients (3.5%) on #busulfan** monotherapy developed acute leukemia. These figures were within the baseline risk inherent to the disease and did not differ from those observed with #hydroxycarbamide** therapy [63].

Comments: Appendix A3, Table 2.

Criteria for assessing the efficacy and tolerability of PV treatment.

Comments: polycythemia vera is a chronic disease requiring long-term treatment.

Comments: patient management tactics currently depend solely on the clinical-hematological response to therapy. The clinical significance of cytogenetic, molecular, and morphological responses is currently being evaluated in clinical trials (Appendix G9).

Criteria for clinical-hematological response in the treatment of PV.

Complete response: hematocrit <45% without the need for phlebotomy (erythrocytapheresis); platelets ≤400×10⁹/L, leukocytes ≤10×10⁹/L, normal spleen size, absence of disease symptoms (microcirculatory disturbances, pruritus, headache).

Partial response: does not meet the complete response criteria, hematocrit <45% without the need for phlebotomy (erythrocytapheresis) OR response in three or more criteria (leukocytes, platelets, spleen size, disease symptoms).

No response: any response that does not meet the partial or complete response criteria.

Criteria for hydroxycarbamide** resistance and intolerance.

1 Need for phlebotomy to maintain hematocrit <45% after 3 months of hydroxycarbamide** therapy at ≥2000 mg/day OR

2 Uncontrolled myeloproliferation (platelets >400×10⁹/L and leukocytes >10 × 10⁹/L) after 3 months of hydroxycarbamide** therapy at ≥2000 mg/day OR

3 Inability to reduce massive splenomegaly (more than 10 cm below the costal margin on palpation) by 50% from baseline OR

4. Inability to relieve symptoms caused by massive splenomegaly after 3 months of hydroxycarbamide** therapy at ≥2000 mg/day OR

5. ANC <1.0×10⁹/L or platelets <100×10⁹/L or hemoglobin <100 g/L (note: Hb <100 g/L standard threshold, keeping original formatting: <10х10⁹/L) at the minimum dose of hydroxycarbamide** required to achieve a complete or partial response OR

6. Leg ulcers or other hydroxycarbamide**-mediated toxicity (skin and mucosal changes, gastrointestinal symptoms, pneumonitis, fever) at any dose of hydroxycarbamide** [65].

Comments: the question of changing therapy is decided on an individual basis. In cases of satisfactory tolerability and the absence of side effects from first-line therapy, dose escalation of the drug is possible.

Comments: in cases of iron deficiency caused by phlebotomy/erythrocytapheresis or anemia developing as a result of bleeding, the need for iron therapy may be considered in exceptional cases. This therapy should be administered with continuous and careful monitoring of the complete blood count.

3.2 Treatment of essential thrombocythemia

Goals of ET therapy: prevention of thrombotic or hemorrhagic complications; minimization of the risk of disease progression to post-ET myelofibrosis or blastic transformation; control of constitutional symptoms; prevention of complications during pregnancy and surgical procedures [1, 2, 5].

The target platelet count in patients receiving therapy should correspond to the lower limit of normal—400×10⁹/L [1, 2, 6].

Comments: smoking cessation, normalization of blood pressure, correction of hypercholesterolemia and hyperglycemia, weight normalization, and adequate treatment of cardiovascular diseases reduce the risk of thrombotic complications.

Comments: discontinuation of ongoing therapy with #acetylsalicylic acid**, #clopidogrel** must be done in advance (5–7 days before the procedure, in accordance with the pharmacokinetics of the drug used) prior to surgical interventions and resumed afterward [1, 2, 5].

Comments: patients require monitoring; cytoreductive therapy is initiated in the following cases:

· thrombocytosis (platelets >1000×10⁹/L);

·prior to elective surgical procedures;

· disease progression (increase in platelet count >300×10⁹/L over 3 months, onset of splenomegaly, constitutional symptoms);

· complications (thrombosis or bleeding) [1, 2, 71].

Comments: #interferon alfa-2b**—starting dose 1–3 million IU subcutaneously 3 times a week with possible dose adjustment up to 3–10 million IU per injection in divided doses; the administration schedule is also chosen individually based on tolerability (daily, every other day, five days a week, etc.) [138] until a complete or partial response is achieved, followed by maintenance therapy at the minimum dose sufficient to preserve the achieved response [78]; #peginterferon alfa-2b** 45–90 mcg/week [58, 60]

Comments: #interferon alfa-2b**—starting dose 1–3 million IU subcutaneously 3 times a week with possible dose adjustment up to 3–10 million IU per injection in divided doses; the administration schedule is also chosen individually based on tolerability (daily, every other day, five days a week, etc.) [138]

Comments: #interferon alfa-2b**—starting dose 1–3 million IU subcutaneously 3 times a week with possible dose adjustment up to 3–10 million IU per injection in divided doses; the administration schedule is also chosen individually based on tolerability (daily, every other day, five days a week, etc.) until a complete or partial response is achieved, followed by maintenance therapy at the minimum dose sufficient to preserve the achieved response [78, 138];

#Peginterferon alfa-2b** 45–90 mcg/week [58, 60]

#Interferon alfa-2b** enables rapid normalization of the platelet count. The overall (complete and partial) hematologic response rate was 80%. In the majority of patients, #interferon alfa-2b** helps reduce MPN-related pruritus. However, adverse events in almost a quarter of patients may be a reason for discontinuing #interferon alfa-2b** [54, 138]

#Peginterferon alfa-2b** subcutaneously 45–90 mcg/week [58, 60]

The dose of #peginterferon alfa-2b** depends on body weight (Appendix A3, Table 3). Its use allows for a rapid hematologic response—by 2 months of therapy, the complete response rate was 91% [79]. Over the entire follow-up period, the complete hematologic response rate was 86%. Patients who achieved a complete hematologic response showed improvement in constitutional symptoms compared to treatment failure patients (p < 0.01). The JAK2 V617F allele burden decreased from 48.97% (0.45%–74.24%) to 22.1% (0.33%–65.42%). #Peginterferon alfa-2b** is characterized by satisfactory tolerability. No severe adverse events were observed. The incidence of thrombotic events was 2.8% [78–80, 138].

Comments: #interferon alfa-2b**—starting dose 1–3 million IU subcutaneously 3 times a week with possible dose adjustment up to 3–10 million IU per injection in divided doses; the administration schedule is also chosen individually based on tolerability (daily, every other day, five days a week, etc.) until a complete or partial response is achieved, followed by maintenance therapy at the minimum dose sufficient to preserve the achieved response [78, 138];

#Peginterferon alfa-2b** 45–90 mcg/week [58, 60]

One of the factors limiting the prescription of therapeutic doses of drugs is the development of adverse events (primarily hematologic toxicity). Combination therapy (hydroxycarbamide** + anagrelide, hydroxycarbamide** + #interferon alfa-2b**) can be an alternative when hematologic toxicity occurs. The administration of drug combinations makes it possible to reduce dosages and thereby resolve or prevent adverse events (Appendix A3).

Criteria for evaluating the efficacy and tolerability of ET treatment.

Comments: Criteria for clinical and hematologic response in ET treatment are presented in Appendix G10.

Comments: patient management currently depends solely on the clinical and hematologic response to therapy. A molecular response may also be achieved in some patients (Appendix G9). However, the prognostic significance of molecular responses is unknown.

Comments: in routine clinical practice, trephine biopsy should be performed when signs of disease progression appear.

Comments: Criteria for hydroxycarbamide** resistance/intolerance in patients with ET:

· platelet count >600×10⁹/L after 3 months of therapy with hydroxycarbamide** 2000 mg/day (2500 mg/day in patients weighing >80 kg);

· platelet count >400×10⁹/L, leukocyte count <2.5×10⁹/L, at any dose of hydroxycarbamide**;

· platelet count >400×10⁹/L, hemoglobin level <100 g/L, at any dose of hydroxycarbamide**; 

· leg ulcers or other toxic manifestations caused by hydroxycarbamide** at any dose of the drug;

· fever induced by hydroxycarbamide** administration.

3.3 Treatment of primary myelofibrosis

Goals of PMF therapy:

disease control: prevention of progression, increase in overall and progression-free survival;

symptom relief, improvement in quality of life (treatment of anemia and other cytopenias, reduction of splenomegaly, control of constitutional symptoms);

prevention of complications during pregnancy and surgical procedures [1, 5].

The main factors influencing the choice of treatment option are as follows:

· risk group (according to IPSS, DIPSS, DIPSS+, MIPSS, MIPSS70, MIPSS70-plus version 2.0 systems);

· presence and severity of disease symptoms;

·  patient age;

· comorbidities;

· presence of HLA-matched donors and feasibility of allo-HSCT [1, 5, 37, 91, 100, 138].

Comments: Low and intermediate-1 risk. Typically, these are patients with normal or slightly reduced hemoglobin concentration, moderate leukocytosis without blast cells in the peripheral blood, and moderate bone marrow fibrosis. Patients in this group are likely to have a long life expectancy (7–15 years) and a low risk of disease progression with transformation into AML. The use of aggressive treatment methods in such patients is associated with a higher risk of adverse effects than the risk of disease progression. In the absence of constitutional symptoms and complications, watchful waiting alone is often justified [91, 100].  

When choosing treatment tactics for patients younger than 60 years without severe comorbidities within 1–2 years from disease onset, the feasibility of allo-HSCT should be discussed. Therapy should be initiated when symptoms limiting the patient's daily activities appear: correction of anemia with erythropoiesis-stimulating agents (ATC B03XA Other antianemic preparations), relief of tumor intoxication symptoms with glucocorticoids. Rapidly progressive symptomatic splenomegaly, risk of splenic rupture, presence of constitutional symptoms, and ineffectiveness of symptomatic therapy serve as indications for therapy.

Janus kinase (JAK) inhibitors can be recommended as pathogenetic agents. In low-risk patients, Janus kinase (JAK) inhibitors are used in case of progressive and/or symptomatic splenomegaly when hydroxycarbamide** and/or interferons are ineffective. In intermediate-1 risk patients, Janus kinase (JAK) inhibitors are used in the presence of constitutional symptoms or progressive splenomegaly as second- and subsequent-line therapy, i.e., when hydroxycarbamide** or interferons are ineffective for 3–6 months.

Intermediate-2 and high risk (IPSS, DIPSS, DIPSS+). These are patients with clinically significant anemia, high leukocytosis with a shift to blasts, sometimes with thrombocytopenia, pronounced bone marrow fibrosis, and frequently with chromosomal aberrations. Patients in this category have a high risk of blast transformation in the coming years. When choosing treatment tactics for patients younger than 60 years without severe comorbidities, the feasibility of allo-HSCT should be discussed. If allo-HSCT cannot be planned, cytoreductive and symptomatic therapy is administered. Drugs are primarily chosen according to the clinical manifestations of the disease both to improve quality of life and to prolong it. The main prospect for further improving treatment outcomes in patients classified into the intermediate-2 and high-risk groups is the use of Janus kinase (JAK) inhibitors. The administration of Janus kinase (JAK) inhibitors is indicated as first-line therapy in the presence of symptomatic splenomegaly and/or constitutional symptoms combined with significant splenomegaly. For these patients, there are no other drugs for rapid reduction of spleen size and improvement of quality of life [91, 100].

Comments: given the extremely unfavorable prognosis in this group of patients, alternative sources of donor hematopoietic stem cells (haploidentical or partially matched donor) may also be considered.

Patients with low and intermediate-1 risk are also potential candidates for allo-HSCT. At the first signs of disease progression, the issue of performing allo-HSCT should be addressed. In PMF patients from the low- and intermediate-1 risk groups, high molecular risk mutations should be identified.

Patients in the phase of transformation to AML may also be candidates for allo-HSCT after induction therapy according to an AML treatment program or the use of combination therapy with hypomethylating agents (ATC L01BC Pyrimidine analogues) and BCL2 inhibitors (ATC L01XX Other antineoplastic agents) [69].

Comments: The impact of splenectomy on allo-HSCT outcomes is currently not entirely clear and requires further study.

Comments: antineoplastic drugs are generally prescribed as monotherapy at low doses:

Hydroxycarbamide** 10–30 mg/kg/day orally;

#Mercaptopurine** 1–2 mg/kg/day orally;

#Cytarabine** 10–20 mg/m² /day i.m. or i.v., in courses of 10–14 days every month;

Comments: erythropoiesis-stimulating agents (ATC B03XA Other antianemic preparations) are used to correct anemia and reduce transfusion dependence. Their use is more effective when erythropoietin levels are less than 125 IU/L, and in the absence of transfusion dependency and pronounced splenomegaly. The starting dose of #epoetin alfa** or #epoetin beta** is 150 IU/kg 3 times a week; administration of 40,000 IU once a week is also possible [138]. If the response is insufficient after 1–3 months, the dose may be doubled. If there is no response, treatment should be discontinued after 3–4 months. At the same time, taking into account the disease pathogenesis, the overall efficacy of erythropoietin administration is about 56%, and the effect lasts on average for about 1 year [94].

Comments: the initial dose of the drug depends on the platelet count: 15 mg twice daily for patients with a platelet count of 100–200×10⁹/L; 20 mg twice daily for patients with a platelet count >200×10⁹/L. The maximum dose is 25 mg twice daily. The initial dose in patients with a platelet count of 50–100×10⁹/L is 10 mg twice daily. During the first 4 weeks of therapy, the dosage should not be changed [97, 100, 140]. Dose adjustment is carried out based on the safety and efficacy of the treatment. Treatment of patients with PMF should be suspended if the platelet count is <50×10/L and hemorrhagic syndrome develops, or if the absolute neutrophil count drops to <0.5×10⁹/L [97-100]. After recovery of platelet and neutrophil counts, therapy may be resumed at a dose of 5 mg twice daily (Appendix A3, Tables 4, 5); with stable parameters and satisfactory tolerability, the dose may be gradually increased [97-100]. Dose adjustment of the drug is recommended if the platelet count drops below 125×10⁹/L (Appendix A3, Tables 4, 5) [97, 100].

Discontinuation of the drug leads to "cytokine rebound" syndrome, manifested by a rapid return of constitutional symptoms up to systemic inflammatory response and splenomegaly. Therefore, gradual withdrawal of the drug and administration of low-dose glucocorticoids are required [100-102].

Comments: the most frequent adverse events of fedratinib include diarrhea, nausea, anemia, vomiting, fatigue, thrombocytopenia, constipation, etc. Brain damage (encephalopathy) is registered as the most dangerous adverse event reflected in the prescribing information [30, 100]. Fedratinib is approved in the Russian Federation for the treatment of adult patients with PMF, post-PV MF, or post-ET MF of intermediate-2 or high risk.

Comments: in the preoperative period, it is necessary to assess cardiovascular, hepatic, renal, metabolic, and hemostatic risks. Complications develop in 3% of patients after splenectomy, and postoperative mortality is 9%. It is important to note that approximately 20% of patients experience significant postoperative thrombocytosis, which leads to an increased risk of thrombosis. For this reason, it is critical to normalize the platelet count before and after splenectomy and to monitor complete blood count parameters 4–6 times daily in the early postoperative period. In the post-splenectomy period, therapy with hydroxycarbamide** is administered; in case of resistance to it, therapy with #cytarabine** (10–20 mg/m²/day for 10–14 days every month) [138], #mercaptopurine** (1-2 mg/kg/day) [138], #cladribine** (5 mg/m² for 5 days) [141, 142], or ruxolitinib** [138, 140] is used. Careful monitoring of platelet counts and coagulopathy screening (coagulation tests) is advisable during the first week postoperatively. In addition, for the prevention of venous and postoperative thromboses, heparin group drugs are prescribed in prophylactic doses, such as unfractionated heparin** at a dose of 500–1000 IU/h for 7 days [104], or vitamin K antagonists (warfarin**). Abdominal ultrasound (comprehensive) is advisable at 1 week and 1 month after splenectomy to rule out abdominal vein thrombosis.

Long-term complications, such as hepatomegaly, leukocytosis, and blastic transformation, are the result of the natural progression of the disease. Blastic transformation after splenectomy is observed in 10–15% of PMF patients. This is related to patient selection (performing splenectomy in patients with a more severe disease course and longer survival achieved through splenectomy) rather than a true change in disease biology, as there is no reason to believe that the biological fundamentals of the disease caused by pathological proliferation of clonal stem cells undergo changes as a result of splenectomy [104-105].

Comments: the use of low doses (0.5–2.0 Gy, divided into 5–10 fractions) is generally effective. Radiation therapy to the liver and spleen has a short-term (3–6 months) effect and carries a risk of worsening cytopenias; it is mainly performed in patients with contraindications to splenectomy.

Comments: the urgency and volume of transfusion are determined by the degree of circulatory insufficiency rather than the hemoglobin level. The target hemoglobin concentration during blood component therapy should be above 70 g/L, and in the presence of cardiovascular disease, above 90 g/L.

Comments: an indication for platelet concentrate transfusion is a platelet count below 10–20×10⁹/L or thrombocytopenia with the development of hemorrhagic syndrome. In the presence of increased platelet consumption (fever, infections, hemorrhagic syndrome) or secondary coagulopathy due to impaired liver function, it is necessary to maintain the platelet count above 20×10⁹/L. In the presence of signs of disseminated intravascular coagulation or bleeding, the target platelet count maintained via transfusions should be greater than 50×10⁹/L.

Comments: a complete blood count and monitoring of iron metabolism parameters, primarily serum ferritin, are advisable to perform monthly during treatment. The criterion for treatment efficacy is an increase in hemoglobin to normal levels or by more than 15–20 g/L from baseline within a month of therapy. After hemoglobin normalization, it is advisable to continue iron therapy for about 3 months to replenish iron stores in the body. Thereafter, iron metabolism parameters should be monitored every 3–6 months [109].

Comments: long-term use of transfusions in PMF, due to the lack of active iron excretion mechanisms in the body and limited capacity for iron storage in the liver, leads to the development of secondary hemosiderosis after a transfusion of 20–25 doses, characterized by interstitial iron accumulation in organs and tissues. The most common clinical manifestations of hemosiderosis are associated with damage to the heart, liver, pancreas, and retina.

The recommended starting daily dose of deferasirox** is 20 mg/kg. In patients receiving red blood cell transfusions exceeding 14 ml/kg per month (approximately >4 adult units per month), the starting daily dose may be higher at 30 mg/kg. In patients receiving less than 7 ml/kg of red blood cells per month (approximately <2 adult units of blood per month), the starting daily dose may be 10 mg/kg. It is recommended to monitor blood ferritin levels monthly and, if necessary, adjust the dose of deferasirox** every 3–6 months based on changes in ferritin levels. The dose should be adjusted in increments of 5–10 mg/kg. The direction of dose adjustment is determined by treatment efficacy and therapeutic goals (maintaining or reducing iron burden). If the drug is ineffective at a dose of 30 mg/kg (blood ferritin level remains at ≥ 2500 µg/l), the dose should be increased to 40 mg/kg. Doses above 40 mg/kg are not recommended as clinical experience at these doses is limited. Once the target ferritin level is achieved (usually 500–1000 µg/l), a gradual reduction of the dose (also in increments of 5–10 mg/kg) should be planned to ensure that blood ferritin levels are maintained within the target range. If blood ferritin levels are substantially below 500 µg/l, interruption of deferasirox** therapy should be considered [111].

Comments: fever, drenching sweats, and weight loss are frequently the initial manifestations of the disease troubling patients and prompt a significant proportion of them to seek medical attention. Hydroxycarbamide therapy generally somewhat reduces the severity of tumor intoxication but does not completely relieve it. Glucocorticoids and immunostimulants, as well as their combinations, are more effective, leading in many patients to a reduction in cytokine secretion abnormalities and an improvement in general status. Currently, the most effective agents affecting pro-inflammatory cytokine levels are Janus kinase (JAK) inhibitors [97-100].

Monitoring and Evaluation of Treatment Efficacy in PMF

Comments: clinical and hematological response is assessed based on the presence or absence of intoxication symptoms, splenomegaly, and blood parameters, and can be complete or partial, or indicate disease progression. Criteria for determining clinical and hematological response are provided in Appendix G11.

3.4 Therapy of the blast phase of MPNs

MPN blast phase (BP) is the terminal stage of the disease. The risk of BP is 1–4% in ET, 3–7% in PV, and 9–13% in PMF over 10 years of follow-up. A diagnosis of BP is established when ≥20% blasts are detected in the peripheral blood or bone marrow; another criterion for BP is the accumulation of blasts in tissues and organs in the form of myeloid sarcoma (chloroma). The prognosis in MPN BP is extremely unfavorable: 1-year and 3-year overall survival rates do not exceed 20% and 5%, respectively. The choice of therapy strategy in MPN BP is significantly influenced by the patient's age and comorbid conditions.

To date, there are no controlled studies whose results could define optimal induction chemotherapy in patients with MPN BP. All patients who achieve blast reduction, are under 60 years of age, and have no severe comorbidities are indicated for allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, therapy is frequently palliative in nature. The treatment strategy for the blast phase of MPN is determined by patient age and underlying pathology. In patients with a preserved general somatic status, an attempt at course chemotherapy according to acute leukemia treatment regimens may be undertaken, which yields a temporary effect in a small proportion of patients.

Comments: in most cases, treatment is aimed at halting tumor growth and managing complications (blood component transfusion, treatment of infectious complications, etc.). In order to improve patients' quality of life:

#Azacitidine** 75 mg/m² on days 1–7, subcutaneously, or #decitabine - 20 mg/m² on days 1–5, subcutaneously, #venetoclax** - 200 mg (range 100–400 mg), orally daily, days 1–28. The duration of therapy is not defined. On average, patients receive 3 cycles (ranging from 1 to 9 cycles). The probability of achieving an overall response is 53% [84, 140]. In case of resistance to therapy or loss of response, the use of other antineoplastic agents as monotherapy or in combination is possible: therapy with #cytarabine** (10–20 mg/m²/day for 10–14 days each month) [138], #mercaptopurine** (1–2 mg/kg/day) [138], #cladribine** (5 mg/m² for 5 days) [141, 142], etc.

Allo-HSCT with curative intent may be planned in patients younger than 60–65 years in the absence of contraindications. For these patients, human leukocyte antigen (HLA) typing and donor search are mandatory. Allo-HSCT is feasible upon achieving the chronic phase.

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.

Dietary therapy and specific pain management are not applied.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Main areas of rehabilitation: pharmacotherapy; optimization of physical activity; compliance with diet; prevention of stressful situations and overwork; combatting bad habits; sessions with a medical psychologist.

Comments: the foundation of patient medical rehabilitation services is the establishment of a proper lifestyle, as well as dietary therapy, pharmacotherapy, and adequate physical activity. These measures are used in a comprehensive manner, and their nature is selected individually for each patient in all cases.

Comments: clinical-psychological adaptation and neuropsychological rehabilitation include explanatory discussions aimed at forming adequate perceptions in the patient and their relatives regarding the disease, ways to overcome it and its consequences, and the necessity of an appropriate lifestyle—i.e., work, rest, and dietary regimens, and certain habits as risk factors for MPN complications. Clinical-psychological adaptation and neuropsychological rehabilitation are no less important than pharmacotherapy, as patients frequently experience fear of death, depressed mood, anxiety, and sleep disturbances.

5. Prevention and Dispensary Observation

Since the exact etiological causes of MPNs are unknown, there is no known method for reliable prevention.

MPN patients require continuous lifelong follow-up by a hematologist. The frequency of monitoring ranges from 1 to 3–4 times per year.

5.1 Prevention and follow-up care for patients with polycythemia vera

5.2 Prevention and follow-up care for patients with essential thrombocythemia

5.3 Prevention and follow-up care for patients with primary myelofibrosis

6. Organization of Medical Care

Most MPN patients can receive treatment on an outpatient basis; they do not require hospitalization for examination, diagnosis clarification, or conservative therapy at therapeutic doses.

Indications for planned hospitalization:

• examination of patients with a high risk of hemorrhagic complications during invasive procedures;

• selection of individual targeted drug therapy dosing;

• anemic syndrome in severe anemia for blood transfusion therapy;

• surgical treatment of MPN (splenectomy, portacaval shunt creation, endoscopic ligation of esophageal varices);

• complications from ongoing therapy;

• adjustment of therapy upon development of disease complications (bleeding, thrombosis, serositis);

• presence of comorbid conditions worsening the patient's status;

• adjustment of ongoing therapy (selection of dosing for both standard and targeted drugs), modification of ongoing drug treatment;

• preparation for and performance of allo-HSCT.

Indications for emergency hospitalization:

• splenic infarction;

• anemic syndrome, unspecified;

• hemolytic anemia (hemolytic crisis);

• grade III–IV hemorrhagic syndrome;

• profound thrombocytopenia (platelets <20×10⁹/L) in the presence of pronounced hemorrhagic syndrome (including a history thereof);

• acute thrombosis;

• blastic crisis.

Indications for patient discharge from the hospital:

• diagnosis establishment in the absence of indications for therapy;

• treatment regimen determined;

• cessation of disease complications.

7. Additional Information

7.1 Management approaches in surgical interventions

Patients with MPN have a high risk of both thrombotic complications and bleeding during surgical procedures. Prior to elective surgery, it is advisable to prescribe medications to normalize peripheral blood cell counts. All MPN patients undergoing elective surgical interventions require discontinuation of #acetylsalicylic acid**, #clopidogrel**, and all MPN treatment medications in accordance with the drug's pharmacokinetics.

• In the event of postsplenectomy thrombocytosis, it is recommended to prescribe hydroxycarbamide** or anagrelide 1–3 mg daily, orally, prophylactic administration of antithrombotic agents, and prescription of #acetylsalicylic acid** (100 mg/day) to prevent thrombotic complications [36, 41, 49, 71, 73],

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

• Following surgery, it is recommended for all patients with Ph-negative MPNs to undergo thrombosis prevention with daily or more frequent platelet count monitoring based on clinical indications [1, 2, 5, 37, 100, 116].

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

7.2 Thrombohemorrhagic complications and their management in MPN patients

Thrombosis, thromboembolism, and bleeding are the most typical complications of MPN. Thrombotic complications include the following:

• stroke / transient ischemic attacks;

• retinal artery or vein occlusion;

• coronary artery patency disorders;

• pulmonary embolism;

• deep vein thrombosis;

• erythromelalgia.

Risk factors (patient-related):

• age >60 years;

• history of thrombosis;

• platelet count ≥1500×10⁹/L;

• overweight;

• presence of cardiovascular risk factors (smoking, arterial hypertension, hypercholesterolemia);

• smoking;

• presence of thrombophilic risk factors (mutations (polymorphisms) in the prothrombin gene, factor V Leiden, antiphospholipid antibodies) [46].

Risk factors (MPN-specific):

• biochemical and functional platelet abnormalities,

• elevated leukocyte count and their activation,

• presence of JAK2 V617F mutation or another clonality marker [116].

Bleeding is observed at any platelet count, but is particularly frequent with thrombocytosis (>1000×10⁹/L). The use of NSAIDs, primarily #acetylsalicylic acid**, increases the risk of bleeding [118].

Acquired von Willebrand syndrome is an infrequent complication of MPN. It is characterized by pronounced thrombocytosis, normal or prolonged bleeding time, normal concentration of factor VIII and von Willebrand factor with reduced ristocetin cofactor activity, and decreased platelet binding capacity for collagen. In addition, the blood shows a decrease in high-molecular-weight von Willebrand factor oligomers up to their disappearance, which can be mistaken for type II von Willebrand disease. The deficiency of high-molecular-weight von Willebrand factor oligomers is the main cause of bleeding tendency, and the higher the platelet concentration, the lower the blood levels of high-molecular-weight oligomers and the higher the risk of bleeding [117]. It is hypothesized that therapy and platelet count reduction decrease the risk of thrombosis in MPN. Thrombosis prevention using antiplatelet agents, except heparin, is indicated for all MPN patients [1, 2, 37, 100, 116]. An attractive prospect for reducing thrombosis risk is the use of Janus kinase (JAK) inhibitors, particularly ruxolitinib**. In two conducted clinical trials (COMFORT-I and COMFORT-II), ruxolitinib** significantly reduced leukocyte and platelet counts with a concurrent moderate reduction in the JAK2 V617F allele burden [97, 98]. Secondary prevention (after a thrombosis has already occurred) boils down to normalizing blood parameters, clotting system parameters, and prescribing direct and indirect anticoagulants according to indications under the control of the coagulation system [116].

7.3 Myeloproliferative neoplasms and stroke

Stroke is a major contemporary medical and social problem, represented in 88% of cases by ischemic forms of acute cerebrovascular accident (CVA). The high prevalence of stroke among MPN patients ranges from 5% to 20 according to various sources. Furthermore, an earlier onset of CVA, more frequently in young patients (median age 49 years), dictates the need for proactive diagnostic and primary prevention measures at the very earliest, initial stages of the hematological disease [116, 121].

Clinical Presentation of Cerebrovascular Accident

Ischemic CVAs in MPN patients are characterized by marked heterogeneity in terms of their genesis. Potential causes of ischemic CVAs include:

• atherothrombotic occlusion of one of the branches of the main cerebral arteries with the formation of infarctions in areas of compromised vascularization and corresponding neurological deficit;

• arterial hypertension with the subsequent development of intracerebral arteriolosclerosis leading to lacunar stroke, or systemic hemodynamic disturbances resulting in hemodynamic stroke;

• cardioembolic subtype of brain injury in concomitant cardiac pathology.

In the vast majority of observations, stroke in MPN develops as a hemorheological micro-occlusion resulting from a shift in the ratio of blood formed elements to plasma (hematocrit), as well as altered blood flow in intracerebral arteries followed by cerebral ischemia. Frequently, the cortical localization of lesions in the carotid basin system within border-zone areas proceeds asymptomatically as silent strokes [120, 121]. Transient ischemic attacks manifest in the same vascular systems via similar mechanisms, but are limited by a 24-hour time interval and the absence of brain infarction on neuroimaging [123–125].

Venous circulation disorders—cerebral venous thrombosis and dural venous sinus thrombosis with classic manifestations—are also frequent in MPN patients [124–126].

Stroke may be the initial clinical manifestation of the underlying hematological disease [125, 126]. However, most often, cerebral symptoms (cephalea, dizziness, nausea, sensory and/or motor disturbances) may be masked by general asthenization in MPN patients and go unrecognized in a timely manner.

Angioneuroimaging Characteristics

The neuroimaging features in hematological patients are defined by the predominant subcortical localization of focal changes and a relatively high frequency of so-called covert strokes, in addition to symptomatic CVAs. The development of vascular-origin focal changes in the brain parenchyma is associated with decreased perfusion (inadequate blood flow) and predisposes to cognitive dysfunction, which is also regarded as chronic cerebrovascular pathology.

Pathogenetic Therapy

When acute CVA develops, the main strategic directions are reperfusion and neuroprotection. Reperfusion techniques aimed at restoring or enhancing blood flow through vessels in the damaged area include: antithrombotic hemocorrection, as well as endovascular/surgical intervention methods. Antithrombotic hemocorrection includes intravenous administration of medications for thrombolytic therapy in the absence of contraindications, normalization of hemorheological and hemostatic properties and the antithrombotic reserve of the vascular wall using antithrombotic agents, antiplatelet agents (except heparin), and hemodilution. Endovascular/surgical methods include carotid endarterectomy, transluminal balloon angioplasty of the internal/external carotid artery with stenting, local endovascular transarterial thromboextraction, and thrombolytic therapy followed by endovascular interventions (local endovascular transarterial thrombolysis).

Neuroprotection comprises any methods protecting the brain from death resulting from ischemia (neuronoprotection, glioprotection, vasculoprotection).

Patient Management Tactics

If an MPN patient exhibits any of the following symptoms:

• headache,

• dizziness,

• numbness and/or weakness in an arm and a leg,

• transient visual disturbances,

• impaired consciousness.

• initial consultation (examination, appointment) with a neurologist at a specialized facility, magnetic resonance imaging (MRI) of the brain in T2, T2 FLAIR, T1, T2*/SWI, DWI modes, with suspicion of dissection - T1 fs and 3D-TOF computed tomography angiography of cerebral vessels;

• duplex scanning of brachiocephalic arteries with color Doppler flow mapping, assessing the presence and degree of atherosclerotic lesions;

• electroencephalography;

• 24-hour blood pressure monitoring;

• echocardiography; if patent foramen ovale is suspected, transcranial color-coded duplex sonography of cerebral arteries using microembolic signal detection to diagnose right-to-left shunts.

The risk of cerebrovascular events in patients with MPNs increases sharply in the presence of one or more of the following factors:

arterial hypertension,

• atherosclerosis of the main (brachiocephalic) head arteries,

• diabetes mellitus,

• obesity/metabolic syndrome,

• heart rhythm disorders, valvular pathology,

• inherited thrombophilia,

• history of arterial and venous thrombosis,

• age over 60 years.

MPNs represent a difficult-to-diagnose cause of cerebral thrombotic events. High awareness among physicians of various specialties is essential to identify the underlying hematological disorder in patients with persistent abnormalities in the complete blood count.

Patients with cerebral venous thrombosis are recommended to receive oral antithrombotic therapy for at least 6 months in the absence of contraindications. The decision on longer-term administration of antithrombotic agents is made according to indications determined by the hematological disorder, in consultation with a hemostasiology specialist.

Currently, there are no specific guidelines for thrombolysis in patients with MPNs. Indications align with standard guidelines for thrombolytic therapy [126, 127]. To prevent recurrent transient ischemic attacks (TIAs) and recurrent ischemic stroke, MPN patients at high risk for ischemic stroke or other thrombotic events who have previously suffered a cerebrovascular accident are recommended low-dose acetylsalicylic acid** (75–100 mg/day, orally). In the presence of other indications (e.g., atrial fibrillation), reference should be made to relevant clinical guidelines for the primary prevention of cerebrovascular events. For example, in atrial fibrillation, antithrombotic agents are prescribed in the absence of a high bleeding risk [127, 128].

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

7.4 Myeloproliferative neoplasms and pregnancy

Pregnancy planning in patients with MPNs

Given the high risk of miscarriage and pregnancy complications, pregnancy in patients with MPNs should be planned and cleared by a hematologist whenever possible. Women with MPNs who are planning a pregnancy should be co-managed by a hematologist experienced in managing pregnant patients and an obstetrician-gynecologist to assess the risk of pregnancy complications and coordinate an optimal program for complication prevention and MPN treatment. Depending on the maternal vascular complication risk and pregnancy pathology, various treatment options exist—ranging from antiplatelet therapy and heparin preparations to #interferon alfa-2b**. Pregnancy planning is recommended upon achieving clinical and hematological control of the disease. In women with portal hypertension, the feasibility of pregnancy must be decided jointly by the obstetrician-gynecologist, specialized surgeon, and hematologist following a comprehensive evaluation of the patient, including upper gastrointestinal endoscopy (EGD) and ultrasound of the portal system vessels. When planning a pregnancy, all patients with MPNs undergo baseline platelet count monitoring (ideally ≤400–600×10⁹/L) and hematocrit evaluation (≤45%). It is also necessary to evaluate baseline hemostasis parameters, screen for antiphospholipid syndrome, and test for gene mutations associated with high-risk inherited thrombophilias. If the patient is taking antineoplastic drugs (#hydroxycarbamide**, #busulfan**, #anagrelide, etc.), these drugs should be discontinued 3 months prior to conception to avoid teratogenic effects; the same applies to fathers. To maintain the platelet count at no more than 400×10⁹/L, therapy with #interferon alfa-2b** preparations is indicated 3 months prior to pregnancy.

• All women are recommended to initiate antiplatelet therapy with low-dose #acetylsalicylic acid** (50–100 mg daily) 3 months prior to planned pregnancy. In the presence of additional thrombophilia factors and a history of large vessel thrombosis due to MPNs, LMWH anticoagulant therapy at prophylactic or therapeutic doses is recommended [128, 143].

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

Pregnancy in MPNs

Pregnant women and those desiring children constitute a special group among MPN patients, because marked hypercoagulation caused by MPNs during pregnancy is associated not only with venous thromboembolic events (VTEs), but also with early pregnancy loss. Depending on the time of diagnosis, the following clinical scenarios of pregnancy in MPNs are possible:

• pregnancy in a patient with a previously established MPN diagnosis;

• MPN newly diagnosed during pregnancy.

Risk groups for complication development

Pregnant women with MPNs can be categorized into high- and low-risk groups for complications. The high-risk group includes pregnant patients with any of the following factors present.

1. Prior thrombotic complications (venous or arterial thrombosis, bleeding due to the underlying condition [PV/ET]) and the presence of portal hypertension with grade II–III esophageal and gastric varices.

2. Microcirculatory disorders (erythromelalgia, headache, dizziness, hearing loss, visual impairment) or the presence of two or more inherited thrombophilia gene polymorphisms, including the Leiden mutation (activated protein C resistance), FII mutation (G20210A), MTHFR gene mutation (hereditary hyperhomocysteinemia); antithrombin III deficiency, protein C deficiency, and/or acquired forms of thrombophilia (most commonly antiphospholipid syndrome).

3. Complicated pregnancy course potentially caused by the underlying disease:

• early pregnancy loss (≥ 3 episodes);

• antenatal fetal death;

• fetal growth restriction;

• placental abruption with normally positioned placenta;

• severe preeclampsia;

• early and very early preterm delivery;

• postpartum hemorrhage;

• bleeding from esophageal or gastric varices.

4. Women with a blood platelet count >1500×10⁹/L at the time of the current pregnancy.

The low-risk group includes women who have none of the aforementioned factors.

Evaluation algorithm for MPN patients during pregnancy

The evaluation algorithm for MPN patients involves the following tests during pregnancy [129]:

1. Serial blood count monitoring including red blood cells, platelets, white blood cells, differential leukocyte count, total blood hemoglobin level and hematocrit evaluation, and evaluation of the plasma hemostasis system. Testing for intravascular coagulation markers every 2–4 weeks, on day 3, and 4 weeks postpartum to assess the dynamics of hematological parameters and monitor ongoing cytoreductive therapy;

2. To assess the risk of thrombotic and hemorrhagic complications, evaluation and monitoring of hemostasis parameters (soluble fibrin monomer complexes, blood fibrinogen level, activated partial thromboplastin time (APTT), prothrombin index) every 2–4 weeks during pregnancy and on days 3, 14, and 40 postpartum;

3. Additionally, to assess the risk of thrombotic complications at registration, a single assessment of natural anticoagulants (antithrombin III activity, blood protein C level, protein S activity) and the primary hemostasis/platelet component (platelet aggregation analysis using pharmacological agonists) is required;

4. To assess the risk of thrombotic complications, screening for inherited and acquired thrombophilia is performed if the disease is newly diagnosed during pregnancy or was not performed prior to pregnancy; this includes:

• diagnosing antiphospholipid syndrome — testing for lupus anticoagulant, blood anticardiolipin antibodies (IgG, IgM), and anti-beta-2-glycoprotein antibodies (IgG, IgM);

• testing for mutations in genes associated with high-risk hereditary thrombophilia: molecular genetic testing for the G1691A mutation in the factor V gene (Leiden mutation in coagulation factor V), determination of the prothrombin G20210A polymorphism in the coagulation factor II gene;

• blood homocysteine level testing.

5. If the disease manifested during pregnancy, it is necessary to perform molecular genetic testing — molecular genetic testing for markers of Ph-negative myeloproliferative neoplasms (mutations in the Jak2, MPL, and CALR genes), which allows diagnosing the presence of MPNs in the female patient.

6. Fetal ultrasound twice in each trimester;

7. Ultrasound Doppler of uteroplacental blood flow every 4 weeks, starting from the 22nd week every 4 weeks until the 33rd week, then as clinically indicated;

8. Fetal cardiotocography from the 33rd week every 2–3 weeks, after the 37th week — once every 1–2 weeks to assess the condition of the fetus;

9. To assess the condition of the abdominal organs, an abdominal ultrasound (complex) is performed with determination of the dimensions of the liver, spleen, and the diameter of the portal vein in the 1st–2nd trimester of pregnancy;

10. MRI allows a clearer determination of shunt lumens and assessment of portal blood flow, as well as identification of the degree of parenchymal liver damage and changes in the spleen (if indicated);

11. X-ray examination of the esophagus, stomach, and duodenum with mandatory shielding of the abdomen allows determining the extent of varices along the length of the esophagus, the state of the lower esophageal sphincter, and its functional capabilities (as indicated);

12. EGD is performed as indicated. This is a visual method that allows better than others to determine the presence of varices in the esophagus and stomach, their severity, as well as portal hypertensive vasculopathy and gastropathy, and is the method of choice for differential diagnosis in cases of ongoing or stopped gastrointestinal bleeding.

Management of Patients with MPNs During Pregnancy

Management of patients with MPNs during pregnancy should aim to prevent vascular complications and control thrombocytosis. Currently, the use of drugs that do not cross the placental barrier and are non-teratogenic has significantly improved the quality of life, prognosis, and outcomes of these diseases, and has contributed to the maintenance of pregnancy and a reduction in the rate of complications in patients. Therapeutic options for MPNs during pregnancy include antithrombotic treatment, anticoagulant therapy, phlebotomy for PV, interferons, and B vitamins. Hematocrit levels must be maintained within the normal range appropriate for pregnancy. Increased plasma volume often leads to a decrease in hematocrit and platelet count in the 2nd trimester, after which these parameters rise again in the postpartum period, creating an increased risk of thrombosis in the first 6 weeks postpartum. Close monitoring of blood counts is crucial during this period. To reduce platelet counts during pregnancy, women from the high-risk group for vascular complications will require treatment. If therapy aimed at reducing the platelet count is necessary, recombinant #interferon alfa-2b** is used as the safest treatment option. Numerous studies confirm the absence of embryotoxic and teratogenic effects of #interferon alfa-2b** on the fetus [128, 129, 138, 143].

Algorithm for prescribing #interferon alfa-2b** preparations: in case of thrombocytosis (platelets >400×10⁹/L and <600×10⁹/L), administration of #interferon alfa-2b** should be continued if this treatment was already administered before pregnancy and/or there is a high thrombogenic risk; in case of thrombocytosis (platelets >600×10⁹/L), #interferon alfa-2b** is administered at a dose of 9–21 million IU per week subcutaneously, which allows maintaining the platelet count ≤ 450×10⁹/L [129, 138, 143].

#Acetylsalicylic acid** is used at a dose of 100 mg/day in all women with MPNs throughout pregnancy [129, 138]. Taking into account the pathogenesis of MPNs and changes in the hemostatic system during pregnancy, #acetylsalicylic acid** is not used if there is a history of bleeding outside of or during previous pregnancies. Administration of #clopidogrel** is recommended in case of intolerance to #acetylsalicylic acid** or the development of resistance at a dose of 75 mg/day [129, 138]. As anticoagulant therapy, LMWHs in prophylactic or therapeutic doses are recommended according to clinical guidelines for the prevention of VTEO [129, 138].

Indications for anticoagulant therapy (in combination with cytoreductive and antiplatelet therapy):

• high-risk thrombophilia and/or antiphospholipid syndrome;

• history of major vessel thrombosis;

• reproductive losses (3 spontaneous miscarriages at gestational age <12 weeks, ≥1 miscarriage at gestational age >12 weeks, antenatal fetal death);

• severe complications in previous pregnancies (fetal growth restriction, preeclampsia, or other signs of placental insufficiency).

In the absence of a sufficient effect from the ongoing therapy, extracorporeal treatment methods are used in special cases: plasmapheresis and erythrocytapheresis.

Indications for plasmapheresis in women with MPNs during pregnancy:

• presence of antiphospholipid syndrome refractory to drug therapy, along with MPN;

• pronounced hypercoagulation in the presence of additional thrombophilia factors refractory to drug therapy.

Plasmapheresis is performed in a volume of 300–400 mL every 1–2 days, for a total of 2–7 sessions. Plasma replacement is performed using colloidal and crystalloid solutions (B05BA Solutions for parenteral nutrition, B05BB Solutions affecting the electrolyte balance). The ratio of the volume of removed plasma to the volume of plasma-substituting solutions during pregnancy is 1:1,2; human albumin** is used as a 10% or 20% solution in an amount of 100 or 50 mL, respectively.

Indications for erythrocytapheresis in women with MPNs during pregnancy: erythrocytosis (erythrocytes >5.5×10¹²/L) and hematocrit greater than 45% in PV newly diagnosed during pregnancy. Throughout pregnancy and the postpartum period, women with MPNs are recommended a complex of B vitamins.

Prior to delivery, all pregnant women with MPNs undergo thrombotic complication prophylaxis:

• wearing medical compression hosiery during labor and delivery;

• discontinuation of #acetylsalicylic acid** preparations 7–14 weeks before delivery [129];

• performance of regional analgesia (during labor at the woman's request) or anesthesia (during cesarean section) no earlier than 12 hours after the last prophylactic dose of LMWH and no earlier than 24 hours after the last therapeutic dose of LMWH;

• in planned cesarean section, administration of LMWH in prophylactic doses is stopped 24 hours before it and resumed 3 hours after its completion (or 4 hours after removal of the epidural catheter).

The postpartum period is the most dangerous period for the development of VTEOs. Hemostatic changes characteristic of pregnancy persist for 6 weeks postpartum. The management tactics for the postpartum period consist of VTEO prophylaxis and include the following [129]:

• continue administration of #interferon alfa-2b** if this treatment was administered during pregnancy and/or there was a high thrombogenic risk, in order to maintain a normal platelet count and reduce the risk of VTEO [129, 143];

• continue #acetylsalicylic acid** at a dose of 50–100 mg/day for all patients with MPNs during the 6-week postpartum period. Not used if there is a history of bleeding outside of or during previous pregnancies [129, 143];

• LMWHs in prophylactic doses for 6 weeks postpartum in the presence of additional thrombophilia factors, a history of major vessel thrombosis due to the presence of MPNs, as well as other VTEO risk factors [129, 138, 143];

• suppression of lactation according to standard regimens if IFN alfa-2b therapy is necessary, given that treatment with #interferon alfa-2b** preparations during breastfeeding leads to thrombocytopenia in newborns as the drug penetrates into breast milk [128, 129];

• prescription of a complex of B vitamins to all patients throughout the postpartum period [128, 129];

• compression hosiery must be worn for 6 weeks postpartum.

The effectiveness of treatment is confirmed by the maintenance of clinical and hematological remission of the disease, which is determined by objective examination data, blood parameters, abdominal ultrasound results (liver and spleen size), and bone marrow histological examination. With appropriately selected treatment, a normal course of pregnancy and childbirth is possible. Pregnancy does not affect the course of MPNs. The physical development of children and the frequency of congenital and acquired neonatal pathologies in women with MPNs do not differ from those in the general female population [129].

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Melikyan Anait Levonovna, Doctor of Medical Sciences, Head of the Department of Standardization of Treatment Methods for Hematological Diseases at the National Medical Research Center for Hematology of the Russian Ministry of Health, member of the National Hematological Society association for the promotion of hematology and bone marrow transplantation development.

2. Subortseva Irina Nikolaevna, Candidate of Medical Sciences, Senior Researcher at the Department of Standardization of Treatment Methods at the National Medical Research Center for Hematology of the Russian Ministry of Health.

3. Alla M. Kovrigina, Doctor of Biological Sciences, Head of the Department of Pathology, National Medical Research Center for Hematology of the Russian Ministry of Health, Professor at the Institute of Clinical Morphology and Digital Pathology, Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University), member of the Presidium of the Russian Society of Pathologists, member of the Presidium of the Russian Society of Oncohematologists, member of the European-American Working Group for Bone Marrow Pathology.

4. Vasily A. Shuvaev, Doctor of Medical Sciences, Head of the Department of Hematology and Chemotherapy, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Center for Radiology of the Russian Ministry of Health, Professor at the I.A. Kassirsky and A.I. Vorobyov Department of Hematology and Transfusiology, Russian Medical Academy of Continuous Professional Education, Professor at the Department of Internal Diseases, Institute of Engineering Physics for Biomedicine, National Research Nuclear University MEPhI.

5. Elena V. Morozova, Doctor of Medical Sciences, Head of the Department of Oncology, Hematology and Transplantology for Adolescents and Adults, R.M. Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov First Saint Petersburg State Medical University.

6. Elza G. Lomaia, Candidate of Medical Sciences, Head of the Research Laboratory of Immuno-Oncology, Almazov National Medical Research Center of the Russian Ministry of Health.

7. Vadim V. Baykov, Doctor of Medical Sciences, Professor, Head of the Pathomorphology Laboratory, R.M. Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov First Saint Petersburg State Medical University of the Russian Ministry of Health.

8. Olga Yu. Vinogradova, Doctor of Medical Sciences, Professor at the Department of Oncology, Hematology and Radiation Therapy, Pirogov Russian National Research Medical University of the Russian Ministry of Health, Deputy Head of the Moscow City Hematological Center, Botkin Moscow Multidisciplinary Clinical Research Center of the Moscow Healthcare Department, Chief Researcher at the Department of Cooperative Studies of Hematological Diseases in Adolescents and Adults, D. Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Russian Ministry of Health.

9. Elena A. Gilyazitdinova, Hematologist at the Department of Treatment Method Standardization, National Medical Research Center for Hematology of the Russian Ministry of Health.

10. Sergey V. Gritsaev, Doctor of Medical Sciences, Head of the Center for Outpatient Oncological Care, City Hospital No. 15, Saint Petersburg.

11. Tatyana I. Ionova, Doctor of Biological Sciences, Professor, Pirogov Clinic of High Medical Technologies, Saint Petersburg State University.

12. Alina V. Kokhno, Candidate of Medical Sciences, Hematologist, Head of the Department of Diagnostics and Treatment of Hematological Diseases, Head of the Clinical and Diagnostic Department of Hematology and Myeloid Neoplasms, National Medical Research Center for Hematology of the Russian Ministry of Health.

13. Polina I. Kuznetsova, Candidate of Medical Sciences, Researcher at the 1st Neurological Department, Research Center of Neurology.

14. Larisa A. Kuzmina, Candidate of Medical Sciences, Head of the Department of Hemoblastosis Chemotherapy, Bone Marrow and Hematopoietic Stem Cell Transplantation, National Medical Research Center for Hematology of the Russian Ministry of Health.

15. Irina S. Martynkevich, Doctor of Biological Sciences, Head of the Research Center for Cellular and Molecular Pathology, Russian Research Institute of Hematology and Transfusiology of the Federal Medical-Biological Agency.

16. Tatyana A. Mitina, Doctor of Medical Sciences, Leading Researcher, Head of the Department of Clinical Hematology and Immunotherapy, Moscow Regional Research Clinical Institute named after M.F. Vladimirsky.

17. Evgenia S. Polushkina, Candidate of Medical Sciences, Senior Researcher at the Institute of Obstetrics, V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology of the Russian Ministry of Health.

18. Tatyana I. Pospelova, Doctor of Medical Sciences, Professor, Head of the Department of Therapy, Hematology and Transfusiology, Faculty of Advanced Training and Retraining of Physicians, Novosibirsk State Medical University of the Russian Ministry of Health.

19. Manana A. Sokolova, Candidate of Medical Sciences, Hematologist at the Clinical and Diagnostic Department of Hematology and Myeloid Neoplasms, National Medical Research Center for Hematology of the Russian Ministry of Health.

20. Andrey B. Sudarikov, Doctor of Biological Sciences, Head of the Department of Molecular Genetics, National Medical Research Center for Hematology of the Russian Ministry of Health.

21. Marine M. Tanashyan, Doctor of Medical Sciences, Professor, Corresponding Member of the RAS, Deputy Director for Science, Research Center of Neurology.

22. Anna G. Turkina, Doctor of Medical Sciences, Professor, Head of the Clinical and Diagnostic Department of Hematology of Myeloproliferative Diseases, National Medical Research Center for Hematology of the Russian Ministry of Health.

23. Yury V. Shatokhin, Doctor of Medical Sciences, Professor, Head of the Department of Hematology and Transfusiology, Faculty of Advanced Training and Professional Retraining of Physicians, Rostov State Medical University of the Russian Ministry of Health.

24. Roman G. Shmakov, Doctor of Medical Sciences, Professor of the RAS, Director of the Moscow Regional Research Institute of Obstetrics and Gynecology named after Academician V.I. Krasnopolsky, Head of the Department of Obstetrics and Gynecology, Moscow Regional Research Clinical Institute named after M.F. Vladimirsky.

25. Elena N. Parovichnikova, Doctor of Medical Sciences, General Director of the National Medical Research Center for Hematology of the Russian Ministry of Health, Chief freelance Hematologist of the Russian Ministry of Health.

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

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. Hematologists

2. Oncologists

3. General practitioners

4. Neurologists

5. Cardiologists

6. Obstetrician-gynecologists.

Table 1. Level of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

Table 2. Level of Evidence (LoE) grading scale for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Table 3. Grade of Recommendation (GoR) scale for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

Table 1 Treatment of polycythemia vera

Table 2 Ruxolitinib** dose reduction in patients with polycythemia vera

Table 3 Treatment of essential thrombocythemia

Table 4 Initial ruxolitinib** dose in the treatment of myelofibrosis

Table 5. Selection of ruxolitinib** dosage upon resumption of therapy

Table 6. Ruxolitinib** dose adjustment for thrombocytopenia

Appendix B. Physician Action Algorithms

Flowchart 1. Therapy selection algorithm in patients with low-risk primary myelofibrosis

Flowchart 2. Therapy selection algorithm in patients with intermediate-1 risk primary myelofibrosis

Flowchart 3. Therapy selection algorithm in patients with intermediate-2 and high-risk primary myelofibrosis

Flowchart 4. Treatment algorithm for anemic syndrome in patients with PMF

Flowchart 5. Treatment algorithm for splenomegaly in patients with PMF

Flowchart 6. Therapy algorithm for young and middle-aged patients with PV and ET

Appendix C. Patient Information

The diagnosis of Ph-negative MPNs (PV, ET, PMF) is established based on clinical presentation and laboratory/instrumental findings (corresponding peripheral blood changes, bone marrow trephine biopsy histological features, molecular genetic markers, or other evidence of clonal hematopoiesis), while the exclusion of other disorders as a cause of blood system abnormalities is also essential.

The current goals of therapy for PV and ET are to inhibit disease progression, relieve symptoms, and improve patients' quality of life. With proper treatment approach and result monitoring, the life expectancy of patients with PV and ET should not differ from the general population. Treatment of PMF aims to prolong life and prevent complications that severely impair patients' quality of life.

Patients with MPNs require lifelong regular follow-up by a hematologist. The frequency of visits ranges from 1 to 3–4 times per year.

Therapy for all Ph-negative MPNs is based on a risk-adapted strategy. To this end, based on data analysis from large patient cohorts, thrombosis prognostic scores for PV and disease progression risk stratification systems for PMF have been developed. Assessment of the patient's age and comorbidities is essential.

Adherence to medical recommendations and high treatment compliance allow for disease control and prevention of complications. Treatment of patients with Ph-negative MPNs must be carried out exclusively under the supervision of a hematologist, with monitoring of outcomes according to standard response criteria.

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

Appendix G1 MPN-10 Questionnaire

Russian title: MPN-10

Original title (if applicable): MPN-10

Source (official developer website, validated publication): Ionova TI, Vinogradova OYu, Efremova EV, et al. Development and approbation results of the Russian version of the MPN10 symptom assessment questionnaire for patients with myeloproliferative neoplasms considering international recommendations. Clinical Oncohematology. 2020;13(2):176–84. DOI: 10.21320/2500-2139-2020-13-2-176-184

Type (underline):

• rating scale

• index

• questionnaire

• other (specify): questionnaire for assessing the severity of disease-related symptoms and monitoring the efficacy of ongoing therapy.

Purpose: Assessment tool

Contents:

Key (interpretation): Processing of data from the MPN10 questionnaire involves analyzing the severity of each of the 10 symptoms on a 10-point scale and calculating a total symptom score as the mean severity of all symptoms multiplied by 10 (provided the patient answered at least 6 out of 10 questions). The total symptom score ranges from 0 to 100 (higher scores indicate greater overall symptom severity).

Notes (if necessary): Fill out the form below to assess the severity of disease symptoms. Symptom: from 0 to 10 points, where 0 is none and 10 is the worst imaginable severity. Rate fatigue (weariness, tiredness) by circling the one number that best corresponds to the MAXIMUM level of fatigue over the past 24 hours.

Appendix G2 Thrombosis Risk Prognostic Index in PV

Russian title: Prognostic score for thrombosis risk in polycythemia vera

Original title (if applicable): none

Source (official developer website, validated publication): Marchioli R, Finazzi G, Landolfi R, et al. Vascular and neoplastic risk in a large cohort of patients with polycythemia vera. J Clin Oncol. 2005;23(10):2224-2232

Type (underline):

• rating scale

• index

• questionnaire

• other (specify):

Purpose: Assessment tool.

Contents:

Key (interpretation): the incidence of thrombosis is 2.5% per year in the low-risk group, 5% in the intermediate-risk group, and 10.9% in the high-risk group

Notes: all patients with polycythemia vera should be assigned to a risk category to determine therapeutic strategy

Appendix G3 Overall Survival Scoring Index for PV Patients

Russian title: Overall survival prognostic score in patients with PV

Original title (if applicable): none

Source (official developer website, validated publication): Tefferi A, Rumi E, Finazzi G, Gisslinger H, Vannucchi AM, Rodeghiero F, et al. Survival and prognosis among 1545 patients with contemporary polycythemia vera: an international study. Leukemia. 2013;27(9):1874-81. doi: 10.1038/leu.2013.163.

Type (underline):

• rating scale

• index

• questionnaire

• other (specify):

Purpose: Assessment tool.

Contents:

Key (interpretation): Based on the total score, all patients are divided into 3 groups: low risk (0 points), intermediate risk (1 or 2 points), and high risk (≥3 points). Differences in survival were found between the groups. Median overall survival was 27.8 years for the low-risk group, 18.9 years for the intermediate-risk group, and 10.7 years for the high-risk group.

Appendix G4. International prognostic score for arterial thrombosis risk in essential thrombocythemia (IPSET-thrombosis)

Russian title: WHO International Prognostic Score for Thrombosis in World Health Organization-Defined Essential Thrombocythemia

Original title (if applicable): (IPSET-thrombosis)

Source (official developer website, validation publication): Barbui T, Vannucchi AM, Buxhofer-Ausch V, De Stefano V, Betti S, Rambaldi A, Rumi E, Practice-relevant revision of IPSET- thrombosis based on 1019 patients with WHO-definedessential thrombocythemia. Blood Cancer J. 2015;5:e369. doi: 10.1038/bcj.2015.94.

Type (underline):

• rating scale

• index

• questionnaire

• other (specify):

Purpose: Assessment tool.

Contents:

Key (interpretation): patient can be classified as low risk if 0 or 1 point, intermediate risk if 2 points, high risk if 3 or more points

Appendix G5 International Prognostic Scoring System for PMF (International Prognostic Scoring System, IPSS)

Russian title: International Prognostic Scoring System for PMF

Original title (if applicable): International Prognostic Scoring System, IPSS

Source (official developer website, validation publication): Cervantes F. New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. Blood. 2009. 113(13). 2895-901.

Type (underline):

• rating scale

• index

• questionnaire

• other (specify):

Purpose: Assessment tool.

Contents:

Key (interpretation):

0 points - low risk;

1 point – intermediate-1 risk;

2 points – intermediate-2 risk;

3 points or more – high risk.

Appendix G6 Dynamic International Prognostic Scoring System for PMF (Dynamic International Prognostic Scoring System, DIPSS)

Russian title: Dynamic International Prognostic Scoring System for PMF

Original title (if applicable): Dynamic International Prognostic Scoring System, DIPSS

Source (official developer website, validation publication): Gangat N., Caramazza D., Vaidya R. et al. DIPSS Plus: A Refined Dynamic International Prognostic Scoring System for Primary Myelofibrosis That Incorporates Prognostic Information From Karyotype, Platelet Count, and Transfusion Status. Journal of Clinical Oncology. 2011. 29(4). 392-7.

Type (underline):

• rating scale

• index

• questionnaire

other (specify):

Purpose: Assessment tool.

Contents:

Key (interpretation):

0 points - low risk;

1 - 2 points – intermediate-1;

3 - 4 points – intermediate-2;

5 - 6 points or more – high risk.

Appendix G7 Dynamic International Prognostic Scoring System Plus for PMF (Dynamic International Prognostic Scoring System+, DIPSS+)

Russian title: Dynamic International Prognostic Scoring System Plus for PMF

Original title (if applicable): Dynamic International Prognostic Scoring System+, DIPSS+

Source (official developer website, validation publication): Gangat N., Caramazza D., Vaidya R. et al. DIPSS Plus: A Refined Dynamic International Prognostic Scoring System for Primary Myelofibrosis That Incorporates Prognostic Information From Karyotype, Platelet Count, and Transfusion Status. Journal of Clinical Oncology. 2011. 29(4). 392-7.

Type (underline):

• rating scale

• index

• questionnaire

• other (specify):

Purpose: Assessment tool.

Contents:

Key (interpretation):

0 points - low risk

1 point – intermediate-1

2 - 3 points – intermediate-2

4 points or more – high risk

Appendix G8. Criteria for clinical and hematological response in PV treatment

Appendix G9. Assessment of molecular response during PV and ET treatment

Appendix G10 Criteria for clinical and hematological response in ET treatment

Appendix G11 Clinical and hematological response criteria for the treatment of PMF (PMF, post-PV MF, post-ET MF)

Appendix G12 Frequency of follow-up examinations for patients with myeloproliferative neoplasms (polycythemia vera, essential thrombocythemia, primary myelofibrosis)