Primary myelofibrosis prognosis. Complications of idiopathic myelofibrosis during therapy. Clinical picture: symptoms

Primary myelofibrosis (PMF), refers to clonal myeloproliferative neoplasms (MPN).

It is characterized by a peripheral blood leukoerythroblastic pattern, poikilocytosis in the form of teardrop-shaped erythrocytes, and extramedullary hematopoiesis with progressive hepatosplenomegaly, in particular, due to the mobilization of hematopoietic precursor cells from the bone marrow to the liver and spleen.

Such changes in hematopoiesis are constantly associated with profound modification of the stroma in the bone marrow and spleen, which demonstrates the presence of myelofibrosis, osteosclerosis, and neoangiogenesis.

The incidence is 0.73 for men and 0.40 for women per 100,000 population per year.

Although molecular defects associated with the development of primary myelofibrosis (PMF) its pathogenesis remains unclear. Attached great importance point mutations of TK JAK2, which are detected in PMF in 90% of cases.

The most common anomalies that can cause this type of myeloproliferation are:

Multipotency of hematopoietic cells of a clone with myeloid and lymphoid differentiation, although absolute lymphopenia can be observed in peripheral blood;
- progressive predominance of clonal hematopoiesis over normal polyclonal hematopoiesis, resulting in overproduction of one or more lines of mature blood cells;
- hypersensitivity of hematopoietic progenitor cells to growth factors,
- involvement of the megakaryocytic lineage with its hyperplasia and dysplasia, resulting in excessive production of certain cytokines and chemokines;
- the presence of TK JAK2 mutations in thrombopoietin receptors of MPL genes, which leads to a pronounced activation of the JAK/STAT5 protein involved in proliferation and hypersensitivity glucocorticosteroids (GSK) to growth factors;
- Presence of cytogenetic abnormalities.

In primary myelofibrosis, a 200-fold increase in the number of circulating CD34+ cells in the peripheral blood and their presence in large numbers in the spleen was noted, which is not observed with true polycythemia (IP) and essential thrombocythemia (THIS).

Also defined increased amount endothelial precursors and mesenchymal stem cells in the blood and spleen in patients with PMF, which reflects a violation of their adhesion to bone marrow stromal cells. This leads to the development of myeloid metaplasia and angiogenesis in the spleen.

The development of myelofibrosis is the result of a complex process involving changes in fibroblasts, which leads to impaired expression of adhesion molecules and increased deposition of extracellular matrix components.

This accumulation leads to excessive release/leakage of growth factors in the bone marrow by the cells of the pathological hematopoietic clone, in particular, during necrosis of megakaryocytes. In addition, platelet factor 4, platelet-derived growth factor (PDGF), transforming growth factor and vascular endothelial growth factor (VEGF) activate both mesenchymal cells, leading to myelofibrosis, and endothelial cells, leading to angiogenesis.

There is a hypothesis that increased production of osteoprotogerin by stromal and endothelial cells can lead to unbalanced production of osteoblasts, as a result of which osteosclerosis is often combined with myelofibrosis.

In the proliferation of HSC progenitors and their hypersensitivity to growth factors, anomalies in signaling connections between stem hematopoietic pluripotent cells, in particular, resulting from mutations of JAK2 TK and MPL genes, can play a role. Of course, "specificity" pathological processes is the result of changes in the interaction between hematopoietic and stromal cells.

Stromal cells are conditioned by tumor hematopoietic cells and, accordingly, stromal cells in the pathology of the microenvironment are involved in supporting the clone, which leads to an imbalance in normal hematopoiesis.

By ignoring the control of the HSC compartment by the microenvironment in homeostasis, neoplastic HSCs can survive in organs (liver, spleen) that are unable to support hematopoiesis in adults. In addition, splenic fibroblasts have the ability to maintain neoplastic hematopoiesis in adults and are involved in the proliferation of megakaryocytes in the lymphoid zones, which leads to significant changes in megakaryocytes and lymphocytes (Fig. 4, 5).

Rice. 4. Simplified model of hematopoietic stem cell (HSC) niches

These niches consist of: (1) stromal cells derived from mesenchymal stem cells (MSCs) capable of generating fibroblasts, osteoblasts/osteocytes, and adipocytes; (2) osteoclasts derived from HSCs; and (3) endothelial cells derived from endothelial stem cells (ESCs). Regulatory signals coming from these various niches include intracellular regulatory mechanisms, interaction of adhesion molecules, extracellular matrix (ECM) and microenvironmental components such as calcium (Ca++), oxygen concentration (O2), proteases, and humoral factors including cytokines and chemokines.

Rice. 5. Possible Mechanisms responsible for the pathogenesis of primary myelofibrosis

Since the initial molecular defect in the origin of the pathological lineage is unknown, alterations in pertinent tyrosine kinase signaling lead to amplification of the hematopoietic lineage, consistent with mutations in the JAK2 and MPL genes in a subset of patients with PMF. Changes in the interactions between the clone of CD34+ cells and stromal cells of the hematopoietic microenvironment lead to an increase in the production of cytokines by clonal hematopoietic cells, which leads to degeneration of megakaryocytes and monocytes. An increase in the production of hematopoietic, fibrogenic and angiogenic growth factors supports the proliferation of hematopoietic cells (myeloproliferation), and stimulates myelofibrosis, osteosclerosis and angiogenesis through the activation of stromal and endothelial cells. Release of CD34+ cells from the bone marrow (stem cell mobilization) occurs through various mechanisms, including changes in chemokine receptors and activation of proteases released by activated neutrophils. HSC - hematopoietic stem cells; Mk - megakaryocytes; Mine are monocytes; H - neutrophils; FB - fibroblasts; Region - osteoblasts; Ocl - osteoclasts.

Based on these observations, PMF can be considered as a disease in which the development of a pathological clone is closely associated with changes in the microenvironment. An imbalance between endosteal and vascular niches in the bone marrow may be part of the pathogenesis of the disease.

This dysregulation benefits the proliferation of hematopoietic, mesenchymal and endothelial stem cells with their mobilization from the bone marrow into the blood, leading to an increase in the number of circulating stem cells (SC) and to a progressive decrease in the base of bone marrow hematopoiesis.

SCs migrate to the liver and spleen, to newly formed vascular niches, where they have advantages in proliferation and differentiation, since normal HSCs do not survive in a pathological microenvironment. This process ultimately leads to the development of extramedullary hematopoiesis and hepatosplenomegaly.

HSCs in PMF belong to a pathological clone and remission in young patients with HSCT determines the opinion that genetic damage to HSCs is part of the pathogenesis of this disease. Therefore, primary myelofibrosis can be considered as a disease of HSC (Fig. 6). Data on the regulation of HSCs by the microenvironment suggest the leading role of disturbances in their relationships in the development of this disease.

Rice. 6. Release of stem cells from the bone marrow into the niches of the spleen/liver in PMF

Due to unknown molecular mechanisms, clonal hematopoietic stem cells proliferate and generate differentiated cells leading to a hyperproliferative bone marrow state early in the disease. Dystrophic megakaryocytes produce or release various factors growth and protease leading to myelofibrosis and imbalance between endosteal and vascular niches. This imbalance leads to a predominant proliferation of stem cells (SCs), including hematopoietic, endothelial and mesenchymal stem cells (HSCs, ESCs and MSCs) and their Bbixofle into the blood, resulting in an increased number of circulating SCs followed by bone marrow aplasia. These stem cells colonize the spleen and lead to spleno/hepatomegaly, which is characteristic of PMF.

Clinical picture

Due to increased cellular catabolism,
- arising from insufficiency of bone marrow hematopoiesis,
associated with splenomegaly.

The first group of symptoms include weight loss, fever, hyperuricemia. The latter occurs during massive cytostatic therapy.

Hyperuricemia may be asymptomatic or present with gout urolithiasis(ICB), chronic pyelonephritis . In these cases, it is recommended to take allopurinol 200-800 mg / day, depending on the level of uricemia. An increase in body temperature is due to infection, most often urinary tract or latently flowing acute leukemia.

The causes of anemia, especially in the later stages of the disease, are:

Bone marrow failure
- hypervolemia,
- increased deposition and sequestration of blood cells in the enlarged spleen,
- autoimmune erythrocyte hemolysis,
- iron deficiency and folic acid.

Quantitative insufficiency of hematopoiesis is caused by the replacement of hematopoietic bone marrow with myelofibrosis and osteomyelosclerosis in the presence of adipose tissue, as well as increased deposition and destruction of blood cells in the spleen. Hemodilutional anemia is the result of hypervolemia in splenomegaly. Folic acid deficiency with the presence of macrocytic anemia is observed in the late stage of the disease due to increased consumption of folic acid for enhanced hematopoiesis.

The causes of thrombocytopenic hemorrhagic syndrome are:

Increased deposition and destruction of platelets in the enlarged spleen and liver,
- secondary autoimmune hemolysis of platelets,
- impaired platelet formation due to a reduction in the number of megakaryocytes,
- DIC (consumption thrombocytopenia),
- a combination of these characteristics.

Approximately 30% of patients at diagnosis is determined by hepatomegaly. At the same time, there is no significant impairment of liver function. More characteristic is the development of portal hypertension syndrome with the presence of splenomegaly, varicose veins of the esophagus, ascites and peripheral edema.

One of the causes is myeloid metaplasia in the sinuses of the liver and spleen, reactive fibrosis, and sometimes postnecrotic cirrhosis of the liver. The cause of ascites may also be the implantation of hematopoietic foci on the mesentery and omentum. It is also possible to increase the lymph nodes of the abdominal cavity due to myeloid metaplasia.

The major diagnostic criteria for PMF are (WHO 2008):

Proliferation and atypia of megakaryocytes in combination with reticulin and / or collagen fibrosis; in the absence of reticulin fibrosis in the prefibrotic stage, an increase in the cellularity of BM due to the proliferation of granulocytes and often a narrowing of erythropoiesis are determined;
- no signs of PI, chronic myeloid leukemiaa (CML) BCR-ABL1+, MDS and other myeloid neoplasias; dyserythropoiesis and dysgranulopoiesis (i.e., prefibrotic cell phase) are usually absent;
- the presence of JAK2 V617F or other clonal markers, or in their absence - evidence of primary fibrosis.

Towards minor diagnostic criteriaprimary myelofibrosisassigned:

Leukoerythroblastic picture of peripheral blood with the presence of drop-shaped erythrocytes;
- splenomegaly due to myeloid metaplasia;
- level up lactate dehydrogenase (LDH);
- anemia.

Main diagnostic criterion is the first large criterion, additional - the third large and the second small. These criteria are not designed to diagnose an early stage of the disease, since at first there may be no changes in peripheral blood.

Therefore, the diagnosis of PMF according to the 2008 WHO classification should be based on all three major criteria and, to clarify the prefibrotic cell phase, on 2-1 minor criteria. First of all differential diagnosis carried out with CML, myelofibrosis in the postpolycythemic phase of IP and myelofibrosis in ET.

Treatment of primary myelofibrosis

HU is preferred due to its low leukemia risk. HU is prescribed at a dose of 0.5-1.0 g/day with further transfer to a maintenance dose of 0.5 g once every two days. In the absence of thrombocytosis and leukocytosis, the appointment of prednisolone at a dose of 20-15 mg / day is indicated.

Especially indicated is the appointment of prednisolone in the presence of hemolytic anemia and thrombocytopenia at doses up to 60–90 mg/day, although a hematologic response may be seen at low doses. Recently, GM-CSF in combination with erythropoietin has been used in the treatment of anemia and leukopenia.

It has been shown that bisphosphonates induce apoptosis in tumor cells. The combination of statins with zoledronic acid preparations has an antiproliferative and bone-remodeling effect. In addition to the tumor-apoptotic effect, statins inhibit macrophage activation and the secretion of various proteolytic enzymes, including metalloproteinases.

Zoledronic acid inhibits tumor cell proliferation by increasing immune-mediated cytotoxicity while increasing biological activity hematopoietic microenvironment (Fig. 7).

Rice. 7. Hematopoietic niches: new therapeutic targets for primary myelofibrosis

New therapeutic targets are HSC and JAK-STAT, since the effect of the use of JAK2 inhibitors has been demonstrated. Different cellular and/or extracellular components of hematopoietic niches can become targets, achieving a balance between endosteal and vascular niches, which leads to a change in the output of stem cells. Progress in the treatment of PMF has been achieved with the use of anti-TGF-P, anti-VEGF or inhibitors of their receptors, bone marrow remodeling drugs, fibrosis inhibitors, and metalloproteases (MMPs).

In the treatment of anemic and thrombocytopenic syndromes, splenectomy is also used.

The main indications for its implementation are:

Hemolytic anemia with labeled erythrocyte lifetime less than 11 days,
- thrombocytopenia below 100.0x10%,
- massive splenomegaly with compression complications,
- portal hypertension.
However, splenectomy is contraindicated in:
- the number of platelets is more than 500.0x10%,
- the presence of DIC,
- Significant splenomegaly
- predominant localization of hematopoiesis in the spleen,
- violation of the functions of the heart, liver, kidneys.

The first three contraindications are absolute: splenectomy leads to a significant increase in the number of platelets with high probability development of thrombotic vascular complications.

A cardinal cure for primary myelofibrosis is possible only with the help of allogeneic bone marrow transplantation (allo-TKM) or allogeneic transplantation of hematopoietic stem cells (allo-HSCT). Surgery is appropriate in patients with no adverse factors risks, which include: age over 60 years, hepatomegaly, weight loss, severe thrombocytopenia, blood leukocyte count below 4.0x10% and above 30.0x10%, as well as the presence of cytogenetic abnormalities.

Myelofibrosis (idiopathic myeloid metaplasia, myelofibrosis with myeloid metaplasia) is a chronic and usually idiopathic disorder characterized by bone marrow fibrosis, splenomegaly, and anemia with immature, teardrop-shaped red blood cells. Diagnosis requires bone marrow examination and the exclusion of other causes that may cause secondary myelofibrosis. Supportive care is usually given.

ICD-10 code

C94.5 Acute myelofibrosis

Epidemiology

The peak incidence of idiopathic myelofibrosis occurs between the ages of 50 and 70 years.

Causes of myelofibrosis

Myelofibrosis is characterized by fibrous degeneration of the bone marrow with the loss of hematopoietic cells and the subsequent development of extramedullary hematopoiesis (mainly in the liver and spleen, the size of which increases significantly). This pathology is usually the primary disease, which is probably due to neoplastic transformation of bone marrow multipotent stem cells - these stem cells stimulate bone marrow fibroblasts (this process is not part of neoplastic transformation) to increase the formation of collagen. Myelofibrosis can also occur due to various hematological, oncological and infectious diseases. In addition, myelofibrosis can be a complication of chronic myeloid leukemia and occurs in 15-30% of patients with polycythemia vera and a long course of the disease. A large number of immature erythrocytes and granulocytes enter the bloodstream (leukoerythroblastosis), which may be accompanied by increased activity blood LDH. In the outcome of myelofibrosis, bone marrow hematopoiesis fails with the development of anemia and thrombocytopenia. A rarer variant of this disease is malignant or acute myelofibrosis, which is characterized by more rapid progression; it is possible that this form of the disease is actually true megakaryocytic leukemia.

Conditions associated with myelofibrosis

Myelofibrosis Symptoms

Early stages may be asymptomatic. Splenomegaly may be seen; in later stages, patients may complain of general malaise, weight loss, fever, and infarcts of the spleen may be detected. 50% of patients have hepatomegaly. Lymphadenopathy is sometimes detected, but this symptom is not typical for this disease. Approximately 10% of patients develop rapidly progressive acute leukemia.

Diagnosis of myelofibrosis

Idiopathic myelofibrosis should be suspected in patients with splenomegaly, splenic infarction, anemia, or an unexplained LDH elevation. If a disease is suspected, a general clinical analysis blood and hold morphological study peripheral blood and bone marrow with cytogenetic analysis. Other diseases associated with myelofibrosis (eg, chronic infections, granulomatous diseases, cancer metastases, hairy cell leukemia, autoimmune diseases); for this purpose, a bone marrow examination is usually performed (if appropriate clinical and laboratory data are available).

Blood cells have different morphological structure. Anemia is hallmark disease and tends to progress. Erythrocytes are normochromic-normocytic with slight poikilocytosis, in addition, reticulocytosis and polychromatophilia are observed. Nucleated erythrocytes may be found in the peripheral blood. In the later stages of the disease, erythrocytes are deformed, they may be in the form of a drop; these changes are enough to suspect the disease.

The level of leukocytes is usually elevated, but very variable. As a rule, immature neutrophils are found, and blast forms may be present (even in the absence of acute leukemia). At the onset of the disease, the platelet count may be high, normal, or reduced; with the progression of the disease, there is a tendency to thrombocytopenia. In the peripheral blood, the level of progenitor cells may increase (as detected by counting the number of CD34+ cells).

The bone marrow aspirate is usually dry. Since bone marrow fibrosis is required to confirm the diagnosis, and fibrosis may be unevenly distributed, an uninformative first biopsy should be repeated elsewhere.

Idiopathic myelofibrosis- a very rare disease of stem cells involved in hematopoiesis. Life expectancy in idiopathic myelofibrosis depends on the age of the patient and the treatment regimen.

Idiopathic myelofibrosis - a disease of the hematopoietic system - is more common in people over 60 years of age with a frequency of about 1 in 100,000, without revealing "commitment" to any sex. Synonyms: Formerly known as idiopathic myeloid metaplasia, primary osteomyelofibrosis, or myelofibrosis with myeloid metaplasia. From similar diseases hematopoietic system it is distinguished not only by an excess production of blood cells, but also often by anemia, leukopenia and thrombocytopenia - that is, in fact, inexplicable low level erythrocytes, leukocytes and platelets.

Causes and risk factors for idiopathic myelofibrosis

The nature of idiopathic myelofibrosis is unknown. This is the most mysterious chronic myeloproliferative disorder. Irradiation and exposure chemical substances(toluene, benzene) can play a role and cause bone marrow proliferation, which occurs due to the abnormal addition of collagen fibers. However environmental factors not enough to trigger the development of this disease.

Clinical picture: symptoms

Like other chronic myeloproliferative disorders, idiopathic myelofibrosis can be diagnosed during routine medical examination- due to abnormal blood test results and enlargement of the spleen (splenomegaly) on palpation. In some patients, the only early symptom is thrombocytosis, in others (less often) isolated leukocytosis. In such patients, myelofibrosis may develop within 4 to 7 years, although the result of a bone marrow test may be normal.

Unlike other chronic myeloproliferative disorders, idiopathic myelofibrosis can present with nonspecific symptoms: hot, night sweats weakness, fatigue, weight loss.

Splenomegaly, which can be moderate or severe, is the most common symptom. Hepatomegaly(liver enlargement) is less common and does not occur in the absence of splenomegaly. Lymphadenopathy appears very rarely.

osteosclerosis in the picture of idiopathic myelofibrosis, it proceeds with excessive deposition of minerals on the trabeculae (septa) of the bone marrow and is associated with a violation of the activity of osteocallasts and osteoblasts. Neoangiogenesis (abnormal growth blood vessels) of the bone marrow is considered an additional, but not the main symptom of this disease.

Diagnosis of idiopathic myelofibrosis

Laboratory indicators. Any combination of blood disorders should alert. About 10% of patients have polycythemia vera. Leukocytosis, as a rule, is not to the extent that is observed in chronic myelogenous leukemia. The platelet count may be normal or elevated, but approximately 25% of patients have mild thrombocytopenia. Nucleated red blood cells, myelocytes, promyelocytes, and even blast cells may also be present in the blood.

The JAK2 V617F mutation occurs in approximately 50% of patients, but does not correlate with disease activity. Due to impaired platelet function, these patients are particularly prone to bleeding.

Bone marrow biopsy may reveal abnormally enlarged cells with myeloid hyperplasia, enlargement of large dysplastic megakaryocytes, and, in some patients, dilated bony trabeculae. However, the diagnosis should not be relied solely on histological examinations.

Osteosclerosis can be detected by radiological diagnostics, most often as an increase in density bone tissue in the proximal long bones. ribs, sections of the spine or even the skull. The presence of radiological evidence of osteosclerosis suggests a diagnosis of idiopathic myelofibrosis but does not affect the extent of the disease or prognosis.

Differential diagnosis is required.

Pathologies associated with idiopathic myelofibrosis

Cytogenetic abnormalities are more common in idiopathic myelofibrosis, as in many other myeloproliferative diseases, but they are mostly nonspecific. They include 20q-, 13q-, trisomy 8, trisomy 9, partial trisomy 1q, and 9p reduplication. Trisomy 8 and 12p- suggest a poor prognosis.

Autoimmune disorders are difficult to explain and increase the likelihood of developing infections. Their features are mainly: cryoglobulinemia, circulating immune complexes (usually IgG-antiIgG), rheumatoid factor, polyclonal hypergammaglobulinemia, antinuclear and smooth muscle antibodies, positive Coombs test, etc.

Treatment of idiopathic myelofibrosis

To date, there is no clear treatment regimen for idiopathic myelofibrosis, and allogeneic (foreign) bone marrow transplantation is the only potentially effective therapy. Unfortunately, this approach is effective in patients under the age of 45 with a good prognosis. Transplant-related mortality is higher than 27-32%, while 5-year survival exceeds 60% in patients younger than 45 years. The survival rate for patients older than 45 years is only 14%.

Complications of idiopathic myelofibrosis during therapy

Failed bone marrow transplantation and progressive splenomegaly are two key problems in the treatment of idiopathic myelofibrosis. Anemia is also common due to blood loss, folic acid deficiency, hydremia (hemodilution - high content water in the blood). In the treatment of anemia, prednisolone therapy is effective in some cases.

Cachexia is an inevitable complication. Various strategies have been tried in this situation, including low-dose alkylating agents, hydroxyurea, interferon-alpha, imatinib mesylate ( Iimatinib mesilate) and thalidomide. Alkylating agents such as busulfan and melphalan at 2–4 mg daily have proven effective but are potentially toxic; their use is justified only for specific situations in which other means have not been effective. Hydroxyurea is effective in eliminating leukocytosis and thrombocytosis, but may exacerbate anemia.

Neither interferon nor imatinib has been shown to be effective in idiopathic myelofibrosis - both drugs are toxic in this group of patients. Thalidomide at low doses in combination with prednisolone has been shown to be effective in improving anemia as well as in idiopathic thrombocytopenia, reducing the size of the spleen by an average of 20%.

In some patients, a splenectomy may be necessary. Radiation therapy is used in case of contraindications for surgery, and is quite effective, but fatal complications due to myelosuppression are possible.

Androgens such as danazol have been tried with modest success, but these drugs have side effects which make their long-term use unattractive.

Myelofibrosis- myeloproliferative disease, which is characterized by anemia of varying severity - from moderate to severe, very diverse changes in peripheral blood, bone marrow fibrosis and myeloid metaplasia of the spleen, liver and other organs. The disease results from the proliferation of a mutant clone derived from a hematopoietic stem cell capable of differentiating towards erythrocytes, granulocytes and platelets. Often there is also proliferation of osteoblasts and the formation of new bone tissue. It is not known whether bone marrow fibrosis is a reaction to disturbances in the proliferative activity of hematopoietic cells or a component of such pathological proliferative reactions. Myeloid metaplasia of the spleen, liver, and other organs is usually regarded as a compensatory process; it is possible, however, that it is the result of stem cell proliferation.

Clinical manifestations of myelofibrosis

Myelofibrosis can occur against the background of polycythemia vera or thrombocythemia, but usually it develops as a primary process. It should be emphasized once again that this is a disease of middle-aged and elderly people: the maximum incidence is observed in age group 50-70 years old. Persons of both sexes get sick equally often.

The disease progresses slowly, and because of the latent onset, the diagnosis is often made when the patient is examined for a completely different reason. Symptoms associated with anemia are often observed: drowsiness, weakness and shortness of breath during physical activity. Sometimes the first manifestations of the disease are symptoms caused by an enlarged spleen, namely bloating, discomfort after eating, heartburn, and even swelling in the ankles. Splenomegaly - almost constant feature, the spleen in some cases is slightly enlarged, in others it reaches a huge size, actually occupying the entire abdominal cavity. spleen infarction accompanied acute pain in the left hypochondrium and peritoneal friction noise. Hepatomegaly is often seen. Portal hypertension results from thrombosis of the splenic vein, the formation of extramedullary infiltrates of proliferating cells along the portal tract, or its increased blood supply. Patients with portal hypertension may experience bleeding varicose veins veins of the esophagus and ascites.
Often there are signs of gout. Patients also suffer from itching, which becomes especially painful in warmth. Seizures occur in calf muscles, pain in the bones, and all these symptoms can be very easily attributed to the age of the patient.

Occurring sometimes functional disorders platelets are the cause of intradermal hemorrhages and gastrointestinal bleeding. Approximately 1/3 of patients with myelofibrosis have focal osteosclerosis, usually affecting the bones. axial skeleton and proximal epiphyses of the humerus and thigh bones. Occasionally, other parts of the skeleton, such as the skull, are also affected.

Laboratory data

By the time of applying for medical care anemia is found in 2/3 of all patients. Being mild or moderate in the early stages of the disease, as it progresses, it becomes more severe. Polychromasia, anisocytosis, poikilocytosis are noted, drop-shaped cells appear. Nucleated erythrocytes are often found in peripheral blood. immature granulocytes. Often there is a deficiency of folic acid, caused by insufficient intake of it with food and an increased turnover of blood cells. In case of blood loss, iron deficiency occurs. The number of leukocytes is often increased, they are represented mainly by mature leukocytes, immature forms are also usually found.

The number of platelets may be reduced or increased depending on the stage of the disease. On the early phases their number can reach 1000·10 9 /l. The morphology of platelets is changed; giant forms and fragments of circulating megakaryocytes are found in the peripheral blood smear. As the disease progresses and the spleen enlarges, the number of platelets decreases.

Bone marrow punctures are usually unsuccessful (“dry puncture”), however, due to the focal nature of lesions in myelofibrosis, it is sometimes possible to obtain punctures of hyperplastic areas. For accurate diagnosis trepanobiopsy should be performed ilium. The activity of hematopoietic cells and the degree of bone marrow fibrosis are variable. With the help of the silver plating method, an increase in the number of reticulin fibers can be detected even in hyperplastic fragments.
Level uric acid in the blood with myelofibrosis is usually high.

Course and prognosis of myelofibrosis

Condition of many patients long years remains stable at normal level hemoglobin and minimal splenomegaly. In some patients, the disease is less benign, characterized by a gradual deterioration in health, progression of anemia and splenomegaly. Average term life from the time of diagnosis is 3 years, but many patients live longer. Poor prognostic signs include severe anemia that cannot be corrected with blood transfusions, severe leukopenia, spontaneous bleeding, and fast loss body weight. All of these symptoms may be due to folic acid deficiency. The cause of death is most often progressive anemia, approximately 20% of patients die from acute myeloid leukemia.

Treatment of myelofibrosis

There is no specific treatment. Patients with moderate severe symptoms need only periodic inspection. Anemia is the main reason for starting therapy. A folate deficiency that often occurs responds well to treatment with folic acid. Myelofibrosis is one of the few diseases in which long-term prophylactic folic acid intake at a dose of 5 mg / day is indicated. It should be ensured that the patient is not impaired absorption of vitamin B 12 . Many patients are prescribed androgens, but the latter are not always effective, if the condition improves, then only after a few weeks.
If the anemia is so severe that it causes cardiovascular disorders, then it is necessary to transfuse blood, trying to maintain hemoglobin at the level of 90-100 g / l. However, before embarking on a repeat transfusion program, the general condition of the patient should be carefully assessed. After a blood transfusion, the rise in hemoglobin levels is often less than expected, and eventually its increase becomes smaller and shorter in time, and the improvement lasts only 1-2 weeks. This may be due to the destruction of transfused RBCs in the spleen.

The deposition of blood in the spleen is important reason development of anemia, the degree of deposition must be determined using 51 Cr. Highly effective tool reducing the size of the spleen is myelosan - a short course of treatment with this drug leads to a long-term improvement in the patient's condition.
To reduce the size of the spleen, its irradiation is also used, the results of which are ambiguous. It is not recommended to resort to splenectomy in elderly patients due to high mortality and numerous complications, as well as due to a possible reactive increase in platelet count. The method of embolization through an intra-arterial catheter is safer.
Treatment of patients with hyperuricemia is described above.

Hematology: national guide / ed. O. A. Rukavitsyna. - M. : GEOTAR-Media, 2015. - 776 p.

V.P. Pop

Primary myelofibrosis (PMF, idiopathic myelofibrosis, subleukemic myelosis, osteomyelofibrosis, osteomyelosclerosis, agnogenic myeloid metaplasia with myelofibrosis, idiopathic myeloid metaplasia, myelosclerosis) is a chronic clonal myeloproliferative disease resulting from the transformation of myelopoiesis precursor cell foci of extramedullary hematopoiesis, especially three-growth myeloid metaplasia of the spleen with severe splenomegaly and the appearance of a leukoerythroblastic picture of peripheral blood, drop-shaped form of peripheral blood erythrocytes, symptoms of cytopenia or cytosis.

ICD-10 code: D47.1 (Chronic myeloproliferative disease): myelofibrosis (with myeloid metaplasia); myeloproliferative disease, unspecified; myelosclerosis (megakaryocytic) with myeloid metaplasia.

EPIDEMIOLOGY

The annual frequency of PMF is 0.5-1.5 cases per 100,000 inhabitants (in the USA). The disease is slightly more common in men, usually in the second half of life: the average age of patients exceeds 50 years with a median of about 65 years, the number of cases increases with age. At the same time, there are reports of the onset of PMF in adults younger than 30 years of age and even in adolescence and childhood (more often in girls).

MAIN PATHOGENETIC MECHANISMS OF PRIMARY

MYELOFIBROSIS

Myelofibrosis is considered as a combination of two different but interrelated pathogenetic processes: clonal myeloproliferation as the main driver of the disease and an inflammatory state characterized by changes in the MJ stroma with increased expression of pro-inflammatory cytokines. In 60% of patients with PMF, a JAK2V617F tyrosine kinase mutation was detected, however, JAK2 kinase-mediated signaling pathway impairment and activation of transcription factors are present in all patients, regardless of the JAK2 kinase mutation status. In 5-20%, mutations of other genes are also detected: MPL(5-10%),TET2 and ASXL1- up to 17%, CBL- at 6%, LNK(less than 5%), IDH1/2- up to 4%, and IKZF1 or EZH2. At the same time, bone marrow fibroblasts are polyclonal. The cause of excessive CM fibrosis remains unclear. Myelofibrosis itself is a nonspecific inflammatory response to inflammatory mediators and cytokines produced by the transformed clone and microenvironment cells. The following development mechanisms are distinguished

1. Beyond Mutation JAK2V617F and other genes, 30-40% of patients with PMF have various chromosomal abnormalities, which often indicates a poor prognosis (the most common are deletion of the long arm of chromosomes 20 and 13, trisomy 8 and 9, duplication of parts 1q and trisomy 1q). Trisomy 1q, del(13q), del(20q) and trisomy 8 are detected in 2/3 of patients with chromosomal aberrations. Reciprocal translocation t (6; 10) (q27; q11) in PMF is combined with eosinophilia, trisomy 13 is considered a possible predictor of a rapid fatal outcome. The DIPSS Plus prediction system for an unfavorable karyotype in PMF takes into account the detection (alone or in combination) of trisomy 8, monosomy 7/7q-, iso-chromosome, inversion, 5/5q- deletion, 12p- or 11q23 rearrangement.

2. Various mechanisms leading to the inhibition of apoptosis may contribute to the autonomous proliferation of megakaryocytes in PMF and IP.

3. Proliferation of fibroblasts and osteoblasts due to exposure to growth factors released by both megakaryocytes and platelets, and subsequent early development myelofibrosis, and often osteomyelosclerosis - transforming growth factor β, matrix metalloproteinase 9, as well as other cytokines (platelet growth factor, basic fibroblast growth factor b-FGF, IL-1, circulating vascular factors, colony-stimulating factors). This is supported by the fact that against the background of acquired insufficiency of storage of cytokines in dense granules of platelets, PMF (the so-called "storage disease") can also develop. An important role in the progression of PMF is played by increased angiogenesis due to the vascular endothelial growth factor VEGF, as well as the hepatocyte growth factor HGF. In 70% of patients, there is an increased density of microvessels both in the CM and in extramedullary foci.

4. Myelofibrosis is also promoted by a violation of the immune status - in patients with PMF, elevated level immune complexes and IgG in peripheral blood, monoclonal gammopathy, an increase in the content of immunocompetent cells in histomorphological preparations of BM. Not only the proliferation of a megakaryocyte germ with a maturation defect is important, but also the hyperplasia of monocyte-macrophages, as well as the proliferation of mast cells and basophils.

5. Proliferation of a megakaryocytic germ is not only of bone marrow origin. There is evidence that a significant increase in promegakaryoblasts in CM in PMF may be of extramedullary origin, probably due to splenic hematopoiesis: an increased content of CD34+ was found in the spleen compared to CM. In patients with PMF, the number of circulating CD34+ is also significantly increased in the peripheral blood compared to other cMPDs, which predicts the evolution of the disease towards a blast crisis or acute leukemia.

CLINICAL AND LABORATORY DATA

In 25% of patients with PMF, the disease is asymptomatic and is diagnosed by incidental detection of splenomegaly or changes in peripheral blood. The progression of myelofibrosis correlates with clinical and laboratory data: an increase in anemia and an increase in the size of the spleen. Another characteristic feature is the development of extramedullary foci of hematopoiesis, primarily in the spleen and liver, less often in the lungs (hemoptysis, pulmonary hypertension, respiratory failure), gastrointestinal tract (with bleeding), pleural and pericardial effusion, ascites. There are foci in the mediastinum, the central nervous system - compression spinal cord, focal seizures; compression pain (or neurological defect) in the lower and upper extremities, resistant to analgesics, as well as in the kidneys and bladder (with the appearance of hematuria), peripheral

lymph nodes, mesenteric or retroperitoneal lymph nodes, skin. Clinical manifestations may be:

1) associated with significant splenomegaly (from a feeling of heaviness in the abdomen to periodic acute pain caused by spleen infarction and perisplenitis);

2) caused by excessive cellular catabolism (the so-called general debilitating constitutional symptoms - unmotivated weight loss, increased weakness, unexplained low-grade fever and fever, profuse night sweats, a significant contribution to the development of which is an increased level of tumor necrosis factor TNF, hyperuricemia);

3) arising in connection with insufficiency of CM (anemia, thrombocytopenia).

PMF is the only disease among CMPD with the most diverse symptoms. Depending on the predominance of clinical and laboratory symptoms, 6 variants of PMF were identified: classic, thrombocythemia, erythremic, anemic without reticulocytosis, anemic with reticulocytosis, and thrombocytopenic. Taking into account the evolution of PMF as cMPD - from CM hypercellularity, which is almost indistinguishable at the onset of the disease from that in CML, to CM insufficiency, clinical and histological differences, as well as the associated treatment tactics, it is advisable to distinguish the following phases in the development of PMF for practical activities:

1) proliferative (prefibrotic, early);

2) fibrotic (fibrotic-sclerotic, advanced);

3) transformation into OL (blast phase of PMF). Among the main hematological manifestations pro-

liferative phase PMF is the most common mild leukocytosis. Usually the number of blood leukocytes is in the range from 3x10 9 /l to 25x10 9 /l. Erythrocytosis with plethoric manifestations, gradually progressing to treatment-resistant anemia, mild splenomegaly and/or hepatomegaly, and, often, thrombocytosis are possible, which may resemble ET. In 15% of patients, laboratory signs of disseminated blood coagulation (increased fibrin degradation products) are detected. Relatively rarely, in the proliferative phase, signs of myelophthisis are detected in the peripheral blood (erythroid and myeloid precursors - a leukoerythroblastic picture, and teardrop-shaped poikilocytosis). There is a significantly elevated level of alkaline phosphatase (AP) of neutrophils. CM is characterized by increased cellularity, three-growth hyperplasia with a pronounced shift to the left of neutrophilic granulopoiesis, and initial reticulin myelofibrosis is possible. In the differential diagnosis of plethoric manifestations in patients with PMF with PV, early and significant enlargement of the spleen due to myeloid metaplasia in PMF, the features of megakaryopoiesis in PMF, and the detection of iron deficiency in histological preparations in patients with PV are important.

Fibrotic phase PMF denotes the progression of the disease with the development of significant

myelofibrosis and myeloid metaplasia. In patients at this stage, due to myelofibrosis, it is not easy to aspirate BM (a “dry puncture” is possible), BM hypocellularity, pronounced proliferation of megakaryocytes and their atypism, and an increase in signs of osteosclerosis develop. The symptoms that arose due to CM deficiency (anemia, thrombocytopenia), as well as those associated with severe splenomegaly due to myeloid metaplasia, come to the fore. Splenomegaly (determined in 97-100% of patients with PMF) can be detected 10 years before the developed clinical and hematological picture, and in some patients it can serve as a kind of marker of "predisposition" to PMF even from childhood - in the form of detectable splenomegaly. Hepatomegaly is also a common symptom of PMF and occurs in more than half of patients at the time of diagnosis, however, a significant increase in the liver is usually observed in splenectomy patients. With hepatomegaly, there is sometimes the possibility of developing portal hypertension due to increased blood flow in the liver and intrahepatic obstruction, up to thrombotic block, similar to Budd-Chiari syndrome. Anemic syndrome often comes to the fore in the late stage of the disease. Possible pathogenetic mechanisms of anemia, unequal in value, are: CM deficiency, hypervolemia, hypersplenism, autoimmune hemolysis of erythrocytes, accelerated hemolysis of erythrocytes as a result of paroxysmal nocturnal hemoglobinuria syndrome, enzyme defects, increased lipid peroxidation, iron and folic acid deficiency. With the course of PMF, anemia, splenomegaly (spontaneous ruptures of the spleen may be observed), hemorrhagic syndrome, progressive dysfunction of internal organs, recurrent

infectious complications. Some patients develop pulmonary hypertension with subsequent death from cardiopulmonary disorders.

The proliferative and fibrotic phases are chronic phases of PMF. The evolution of PMF as a disease of the blood system is characterized by a gradual increase in leukocytosis with initially different numbers of leukocytes. In 5-20% of patients over 10 years of the course of PMF may develop secondary OL, resistant to treatment. The development of AL is observed both in cases of progressive leukocytosis and leukopenia, however, most patients do not live to see the development of typical AL.

DIAGNOSTICS

To diagnose PMF, it is necessary to perform a clinical blood test, X-ray or MRI of the bones (heterogeneous increase in density), MRI (CT, ultrasound) of the spleen and liver, aspiration and biopsy of the BM, cytogenetic study of the BM and / or peripheral blood (FISH to detect cytogenetic abnormalities ), PCR of peripheral blood leukocytes (or BM) to detect mutation JAK2V617F,(also to exclude bcr/abl). Previously, the classic criteria for the diagnosis of PMF were splenomegaly, collagenous myelofibrosis, and leukoerythroblastic picture of peripheral blood. In accordance with the WHO criteria (2008), the modern diagnosis of PMF is based on an assessment of clinical, morphological, cytogenetic and molecular data (Table 22.1).

Based on the European consensus classification according to the gradation of myelofibrosis (2005), three degrees of myelofibrosis are distinguished (Table 22.2).

It is also necessary to distinguish between myelofibrosis associated with the progression of PV and ET (Table 22.3.).

Table 22.1. Criteria for the diagnosis of primary myelofibrosis (World Health Organization, 2008)

Table 22.2. European consensus classification according to the gradation of myelofibrosis (Thiele J. et al., 2005)

Table 22.3. Criteria for the diagnosis of post-polycythemic/post-thrombocytic myelofibrosis (International Working Group for Myelofibrosis Research and Treatment criteria, 2008)

*Requires ≥2 criteria.

In the differential diagnosis, diseases that may be the cause of myelofibrosis should be excluded. Some authors noted a decrease in the severity clinical symptoms in patients with PMF over a period of 15 years. Thus, patients diagnosed before 1987 were more likely to have constitutional symptoms (fever, night sweats, weight loss), a higher incidence of splenomegaly and hepatomegaly, and a more frequent phase of osteosclerosis at diagnosis than those who were diagnosed. in the 1990s However, no significant difference was found in prognostic factors and survival between these groups of patients.

One of the main methods for diagnosing PMF remains trephine biopsy followed by histological and/or histomorphometric examination of BM. In connection with the clinical and histological differences between the initial prefibrotic phase of PMF and advanced phases with the development of collagen fibrosis of the CM, a term is used that reflects the histological features of the early (proliferative) phase of PMF - essential megakaryocytic-granulocytic metaplasia. In essential megakaryocytic-granulocytic metaplasia, neoplastic proliferation of disturbed megakaryocytic and granulocytic lineages is observed. Myeloid metaplasia may already occur in this phase. Histopathologically, CM in both essential megakaryocytic-granulocytic metaplasia and classical PMF is dominated by atypical, enlarged, and immature megakaryocytes with cloud-like immature dysplastic nuclei, which are not observed in ET and PV. Features of megakaryopoiesis can be a distinctive diagnostic sign of the proliferative (prefibrotic) phase of PMF, distinguishing between PMF and other cMPDs.

Myelofibrosis in PMF, as in all cMPDs, is a generalized process that progresses at different rates with a heterogeneous degree of severity in different areas of the CM - in the ilium, vertebrae, and sternum. The evolution of CM fibrosis is largely associated with the predominance of large atypical, possibly long-lived and hyperploid megakaryocytes, rather than with an increase in progenitor cells. At the same time, in PMF-associated myeloid metaplasia of the spleen, mega-karyocytopoiesis of the spleen has significant differences.

chia: megakaryocytes of reduced size, their nuclear-cytoplasmic ratio is disturbed, a relative increase in the frequency of promegakaryoblasts is determined; In general, extramedullary megakaryocytopoiesis is characterized by a higher degree of immaturity than bone marrow megakaryocytopoiesis in PMF.

Myelofibrosis accompanies the development of all myeloproliferative diseases and manifests itself in varying degrees of severity with various diseases, and data on its progression remain highly heterogeneous. In the work of M. Adamkov et al. (1998) in the primary diagnosis based on histological semi-quantitative measurement of impregnated reticulin fibers, myelofibrosis was detected in more than 94.4% of patients with PMF, in 27.3% of patients with PV, in 21% of patients with ET, and also in 48% of patients with CML . With repeated biopsies, the most common was the progression of myelofibrosis in PMF.

Myelofibrosis of the CM can occur not only in PMF, but also as an outcome in other cMPDs - IP, ET. At the same time, since BM fibrosis is a non-tumor reaction of BM stromal cells, it can also develop in other diseases not associated with CMPD. Secondary CM fibrosis also occurs in some other oncohematological diseases: CML, hairy cell leukemia, less often - with AL, acute myelofibrosis - a rare malignant disease of the blood system with a poor prognosis; with MDS ("crossover syndrome"), malignant lymphomas. BM fibrosis is also noted in solid tumors with BM metastases (cancer of the prostate, breast, and lungs). Quite often, CM fibrosis develops in diffuse connective tissue diseases (SLE, systemic scleroderma) - as autoimmune CM fibrosis, and occasionally as the coexistence of two diseases - severe CM fibrosis and SLE. Several cases of association of BM fibrosis with visceral leishmaniasis, myeloid metaplasia in tuberculosis, and vitamin D deficiency in rickets have been described.

RISK STRATIFICATION OF PATIENTS WITH PRIMARY MYELOFIBROSIS

Due to the different severity of the disease and the different combination of poor prognosis factors

Several prognostic systems have been developed to assess survival and treatment choices in patients with PMF. According to B. Dupriez et al. (1996), unfavorable prognostic factors included: age over 60 years, hepatomegaly, weight loss, low hemoglobin level, low or very high level of leukocytes, high percentage of circulating blasts, male sex and thrombocytopenia. In the study by S. Ozen et al. (1997) the main indicators that significantly shortened survival were anemia (hematocrit less than 30%) and thrombocytopenia (platelet count less than

The main current staging systems for PMF patients are the international prognostic index IPSS, which can be used in diagnosis, dynamic IPSS (DIPSS), suitable for assessing survival at any point in the disease, age-adjusted index aaDIPSS (age-adjusted DIPSS) for young patients . The IPSS index is based on the results of a survival study by the International Working Group for Myelofibrosis Research and Treatment criteria based on data from 1054 patients with PMF out of 7 international centers, depending on the presence of the following five factors of poor prognosis: age over 65 years (or absent - for patients less than 65 in the aaDIPSS index), presence of constitutional symptoms, hemoglobin level less than 100 g/l, leukocytosis more than 25x10 9 /l, presence of circulating blasts ≥1% At the same time, 525 patients had

the exact amount of observational data from which the DIPSS and aaDIPSS scale is developed. When taking into account three more factors of poor prognosis - thrombocytopenia less than 100x10 9 /l, the need for erythrocyte transfusion and the identification of an unfavorable karyotype (+8, -7 / 7q-, i (17q), inv (3), -5 / 5q-, 12p - or rearrangement 11q23) - for a group of 793 patients, an improved

DIPSS scale - DIPSS Plus, see table. 22.4). Except

In addition, in DIPSS Plus, based on a new study (n=884), an additional group of very high risk was identified, in which factors such as monosomal karyotype, inv (3) / i (17q), circulating blasts> 9%, leukocytes> 40x10 9/L significantly shortened survival compared to the high-risk group: median survival was 9 and 23 months, respectively (DIPSS Plus 2 scale). Other risk factors in these systems (eg, spleen size, as well as various gene mutations, including JAK2, TET2, IDH) not shown negative influence for survival or transformation into acute leukemia.

TREATMENT

Current treatment for PMF still marginally improves overall survival, and is also not curative, although promising research drugs have recently emerged that modify the course of the disease and promote

Table 22.4. Prognostic indices for patients with primary myelofibrosis

schee complete remission. Historically, the treatment of this category of patients was predominantly supportive. Hematopoietic stem cell allotransplantation has become a potentially curative therapy for PMF, but the risk of transplant-related death or severe complications is high, regardless of the intensity of conditioning regimens. Currently, both traditional approaches (hemo-component therapy, androgens, glucocorticoids, thalidomide*, hydroxyurea*, splenectomy, radiation therapy) and research anti-myeloproliferative approaches (inhibitors of JAK2 kinases, histone deacetylase, PI3K/AKT/ mTOR and heat shock proteins) and anti-fibrosis drugs (frezolimumab*, simtuzumab♠), many of which (eg ruxolitinib) are already approved for PMF. Due to the marked differences in clinical course PMF, depending on the phase of the disease, as well as depending on the identified risk groups, there is a significant variability in overall survival, which leads to unequal approaches to treatment, given the often occurring significant side effects of therapy. Based on the risk stratification data according to the DIPSS Plus system (DIPSS Plus 2), a risk-adapted therapy for patients with PMF was proposed.

An algorithm for choosing a treatment strategy for patients with PMF, based on the risk group according to the DIPSS Plus 2 scale, is shown in Fig. 22.1.

The revised response criteria proposed in 2013 by the International Working Group-Myeloproliferative Neoplasms Research and Treatment and European Leukemia Net can be used to assess treatment response (see Table 22.5).

For a group low risk(score 0) and some patients with intermediate-1 risk (score 1) can be observed without any therapeutic intervention. In some patients with symptoms associated with the presence of splenomegaly, extramedullary hematopoiesis, pulmonary hypertension (as manifestations of non-hepatosplenic extramedullary hematopoiesis), weakness, bone pain, pruritus, or thrombocytosis with thrombosis, as well as signs of symptomatic anemia, severe leukocytosis, or constitutional symptoms [profuse night sweats, fever, or weight loss (cachexia)], may already be an indication to start traditional therapy, although it is more appropriate for a group of patients with an intermediate-2 risk (DIPSS Plus - 2-3 points) or high risk(4 or more DIPSS Plus points).

One of traditional methods is the treatment of symptomatic anemia. In a small part of transfusion-independent patients with hemoglobin less than 100 g/l in the absence of significant splenomegaly (palpable spleen less than 5 cm below the edge of the left costal arch), EPO can be used with a low level of serum EPO (in a study by F. Cervantes et al. , 2004, this level was less than 125 IU/L). With splenomegaly more than 5 cm below the left edge of the costal arch, the use of EPO is dangerous due to the possibility of iatrogenic growth

splenomegaly and leukemic transformation. This may be due to the fact that normally EPO binding to its receptor also leads to the activation of JAK2 kinases.

The more traditional treatment for anemia in PMF is with androgens (eg, testosterone enanthate* 400-600 mg IM once a week, fluoxymesterone* 10 mg 2-3 times daily by mouth, or danazol 600 mg/day by mouth) and prednisolone (0.5 mg/kg per day). Androgens are usually used for anemia with low reticulocyte count and failure of prednisolone therapy. Patients with chromosomal abnormalities are less sensitive to androgen treatment. Prednisolone per os It is also used to treat hemolytic anemia. Also effective for anemia are thalidomide* 50 mg/day with or without prednisolone or lenalidomide (10 mg/day) with or without prednisolone (10 mg/day). The response rate for each method mentioned is 15-25%, the duration of the response is 1-2 years. It should be noted that lenalidomide is most effective in the presence of del(5q): during therapy, these patients showed complete remission, so the detection of 5q in patients may serve as a basis for differentiated early prescription of this drug in the presence of PMF symptoms. Another modern derivative of thalidomide*, pomalidomide*, is also effective in anemia, but mainly in JAK2V617F-positive patients with severe splenomegaly. The main side effects: hepatotoxicity and virilizing effects in androgens, peripheral neuropathy in thalidomide * and myelosuppression (neutropenia and thrombocytopenia) in lenalidomide, a tendency to thrombosis (concomitant administration of acetylsalicylic acid is indicated). Thalidomide* with lena-lidomide is contraindicated in women of childbearing age. Glucocorticoids should be avoided in diabetes and osteoporosis, androgens or danazol should be avoided with an increase in the level of prostate-specific antigen or a history of prostate cancer. Red blood cell transfusions are indicated for patients with clinical manifestations of anemic syndrome in order to maintain the hemoglobin level at a level at which the symptoms associated with anemia disappear. Cyclosporine A can also be used to treat transfusion-dependent anemia in patients with PMF.