Proliferative stage of myelofibrosis. Get treatment in Korea, Israel, Germany, USA

Hematology: national leadership/ 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 that occurs as a result of transformation of progenitor cells elopoesis with the development of BM fibrosis, the presence foci of extramedullary hematopoiesis, especially three-line myeloid metaplasia of the spleen with severe splenomegaly and the appearance of a leukoerythroblastic pattern peripheral blood, drop-shaped erythrocytes of peripheral blood, symptoms of cytopenia or cytosis.

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

EPIDEMIOLOGY

The annual incidence of PMF is 0.5-1.5 cases per 100,000 inhabitants (in the United States). The disease is somewhat 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 under 30 years of age and even in adolescence and childhood (more often in girls).

MAIN PATHOGENETIC MECHANISMS OF PRIMARY

MYELOFIBROSIS

Myelofibrosis is considered to be 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 BM stroma with increased expression of proinflammatory cytokines. In 60% of patients with PMF, the JAK2V617F tyrosine kinase mutation was detected, but disruption of the JAK2 kinase-mediated signaling pathway and activation of transcription factors is 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 also IKZF1 or EZH2. At the same time, fibroblasts bone marrow are polyclonal. The cause of excessive BM fibrosis remains unclear. Myelofibrosis itself is a nonspecific inflammatory reaction to inflammatory mediators and cytokines produced by the transformed clone and cells of the microenvironment. The following development mechanisms are distinguished:

1. Besides mutation JAK2V617F and other genes, 30-40% of patients with PMF have various chromosomal abnormalities, which often indicates a poor prognosis (the most common is deletion long shoulder 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 unfavorable karyotype in PMF takes into account the detection (in isolation or in combination) of trisomy 8, monosomy 7/7q-, iso-chromosome, inversion, deletion 5/5q-, 12p- or rearrangement 11q23.

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

3. Proliferation of fibroblasts and osteoblasts due to the influence of growth factors secreted 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-derived growth factor, basic fibroblast growth factor b-FGF, IL-1, circulating vascular factors, colony-stimulating factors). This is confirmed by the fact that against the background of acquired insufficiency of cytokine storage in dense platelet granules, PMF (the so-called “storage disease”) can also develop. Increased angiogenesis due to the vascular endothelial growth factor VEGF, as well as the hepatocyte growth factor HGF, plays an important role in the progression of PMF. 70% of patients have an increased density of microvessels both in the BM and in extramedullary foci.

4. Myelofibrosis is also promoted by impaired immune status - in patients with PMF it is determined increased level immune complexes and IgG in peripheral blood, monoclonal gammopathy, increased content of immunocompetent cells in histomorphological BM preparations. Not only the proliferation of megakaryocyte lineage 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 the megakaryocyte lineage is not only of bone marrow origin. There is evidence that a significant increase in promegakaryoblasts in the BM of PMF may have an extraosseous origin, probably due to splenic hematopoiesis: an increased content of CD34+ was detected in the spleen compared to the BM. In patients with PMF, the number of circulating CD34+ is also significantly increased in the peripheral blood compared to other cMPD, which predicts the evolution of the disease in the direction of blast crisis or acute leukemia.

CLINICAL AND LABORATORY DATA

In 25% of patients with PMF, the disease is asymptomatic and is diagnosed upon accidental detection of splenomegaly or changes in the 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 sign 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), effusion in the pleura and pericardium, 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 splenic 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 made by an increased level of the tumor necrosis factor TNF, hyperuricemia);

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

PMF is the only disease among cMPZ with the most diverse symptoms. Depending on the prevalence of clinical and laboratory symptoms, 6 variants of PMF have been identified: classic, thrombocythemic, erythremic, anemic without reticulocytosis, anemic with reticulocytosis, thrombocytopenic. Considering the evolution of PMF as a cMPD - from hypercellularity of the BM, almost indistinguishable at the onset of the disease from that in CML - to insufficiency of the BM, clinical and histological differences, as well as the associated treatment tactics, for practical purposes it is advisable to distinguish the following phases in the development of PMF:

1) proliferative (prefibrotic, early);

2) fibrotic (fibrotic-sclerotic, advanced);

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

proliferative phase PMF most often occurs with moderate leukocytosis. Typically, the number of blood leukocytes ranges from 3x10 9 /l to 25x10 9 /l. Possible erythrocytosis with manifestations of plethora, gradually developing into treatment-resistant anemia, moderate splenomegaly and/or hepatomegaly, and, often, thrombocytosis, which may resemble ET. In 15% of patients, laboratory signs of disseminated blood coagulation are detected (increased fibrin degradation products). Relatively rarely, in the proliferative phase, signs of myelophthisis are detected in the peripheral blood (erythroid and myeloid precursors - leukoerythroblastic pattern, and guttate poikilocytosis). There is a significantly elevated level of neutrophil alkaline phosphatase (ALP). CM is characterized by increased cellularity, three-line 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 IP, early and significant enlargement of the spleen due to myeloid metaplasia in PMF, features of megakaryopoiesis in PMF, as well as the identification of iron deficiency in histological preparations in patients with IP 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); hypocellularity of the BM, pronounced proliferation of megakaryocytes and their atypism, and an increase in signs of osteosclerosis develop. Symptoms that arise in connection with CM deficiency (anemia, thrombocytopenia), as well as those associated with severe splenomegaly caused by myeloid metaplasia, come to the fore. Splenomegaly (detected in 97-100% of patients with PMF) can be detected 10 years before the full 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, but a significant enlargement of the liver is usually observed in splenectomized 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 a 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, varying in significance, are: BM deficiency, hypervolemia, hypersplenism, autoimmune hemolysis of erythrocytes, accelerated hemolysis of erythrocytes as a result of paroxysmal nocturnal hemoglobinuria syndrome, enzyme defects, increased lipid peroxidation, deficiency of iron and folic acid. As PMF progresses, 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 followed by death from cardiopulmonary disorders.

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

DIAGNOSTICS

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

Based on the European consensus classification for grading 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 IP and ET (Table 22.3.).

Table 22.1. Diagnosis criteria for primary myelofibrosis (World Health Organization, 2008)

Table 22.2. European consensus classification for grading of myelofibrosis (Thiele J. et al., 2005)

Table 22.3. Diagnostic criteria for postpolycythaemic/postthrombocythaemic myelofibrosis (International Working Group for Myelofibrosis Research and Treatment criteria, 2008)

*≥2 criteria required.

In the differential diagnosis, diseases that may cause the development of myelofibrosis should be excluded. Some authors have 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 frequency of splenomegaly and hepatomegaly, and more often the osteosclerosis phase 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 the BM. In connection with the clinical and histological differences between the initial prefibrotic phase of PMF and the advanced phases with the development of collagen fibrosis of the BM, a term is used that reflects the histological features of the early (proliferative) phase of PMF - essential megakaryocyte-granulocytic metaplasia. In essential megakaryocyte-granulocytic metaplasia, neoplastic proliferation of disrupted megakaryocyte and granulocytic lineages is observed. Myeloid metaplasia can already occur at this phase. Histopathologically, CM, both in essential megakaryocyte-granulocytic metaplasia and classic 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 may be a distinctive diagnostic feature of the proliferative (prefibrotic) phase of PMF, distinguishing between PMF and other cMPDs.

Myelofibrosis in PMF, as in all cMPD, is a generalized process that progresses at different rates with heterogeneous severity in different areas of the CM - in the iliac bones, vertebrae and sternum. Evolution of BM fibrosis in to a large extent is associated with a predominance of large atypical, possibly long-lived and hyperploid megakaryocytes, rather than with an increase in progenitor cells. At the same time, in myeloid metaplasia of the spleen associated with PMF, megakaryocytopoiesis of the spleen has significant differences.

chiya: megakaryocytes are reduced in size, their nuclear-cytoplasmic ratio is disrupted, 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 severity at various diseases, and data regarding 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 IP, in 21% of patients with ET, and also in 48% of patients with CML . In repeat biopsies, the most common progression was myelofibrosis in PMF.

BM myelofibrosis can occur not only with PMF, but also as an outcome with other CMPD - 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 fibrosis of the BM also occurs in some other oncohematological diseases: CML, hairy cell leukemia, less often in OL, acute myelofibrosis - a rare malignant disease of the blood system with a poor prognosis; with MDS (“crossover syndrome”), malignant lymphomas. BM fibrosis is also observed with solid tumors with metastases in the BM (cancer prostate gland, breast, lungs). Often, BM fibrosis develops in diffuse connective tissue diseases (SLE, systemic scleroderma) - as autoimmune BM fibrosis, and also occasionally as the coexistence of two diseases - severe BM fibrosis and SLE. Several cases of association of bone marrow 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 varying severity of the disease and different combinations of poor prognosis factors

Several prognostic systems have been developed to assess survival and select treatment for 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 leukocyte level, high percentage of circulating blasts, male gender and thrombocytopenia. In a study by S. Ozen et al. (1997) the main indicators that significantly shortened survival were anemia (hematocrit less than 30%) and thrombocytopenia (platelet level less than

The main modern 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 time of the disease, age-adjusted DIPSS index 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 from 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 sufficient

the exact amount of observational data from which the DIPSS and aaDIPSS were developed. Taking into account three more factors of poor prognosis - thrombocytopenia less than 100x10 9 /l, the need for red blood cell transfusion and the identification of an unfavorable karyotype (+8, -7/7q-, i(17q), inv(3), -5/5q-, 12p - or 11q23 rearrangements) - an improved

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

Moreover, in DIPSS Plus, based on a new study (n=884), an additional group was identified high risk, in whom such factors 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 (for example, spleen size, as well as various gene mutations, including JAK2, TET2, IDH) didn't show negative influence on survival or transformation to acute leukemia.

TREATMENT

Current treatment for PMF still modestly improves overall survival and is not curative, although promising disease-modifying investigational drugs have recently emerged.

Table 22.4. Prognostic indices for patients with primary myelofibrosis

for complete remission. Historically, treatment for this category of patients has been predominantly supportive. Hematopoietic stem cell allotransplantation has emerged as a potentially curative therapy for PMF, but there is a high risk of transplantation-related mortality or severe complications, regardless of the intensity of the conditioning regimen. Currently, there are both traditional approaches (hemocomponent 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 antifibrotic drugs (frezolimumab*, simtuzumab♠), many of which (eg, ruxolitinib) are already approved for the treatment of PMF. Due to the pronounced differences in clinical course PMF, depending on the phase of the disease, as well as depending on the identified risk groups, there is significant variability in overall survival, which leads to unequal approaches to treatment, given the often significant side effects of therapy. Based on risk stratification data using the DIPSS Plus system (DIPSS Plus 2), risk-adapted therapy for patients with PMF was proposed.

The algorithm for choosing a treatment strategy for patients with PMF, based on the risk group according to the DIPSS Plus 2 scale, is presented 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 response to treatment (see Table 22.5).

For the low-risk group (0 points) and some patients with intermediate-1 risk (1 point), observation without any therapeutic intervention is possible. In some patients with symptoms associated with the presence of splenomegaly, extramedullary hematopoiesis, pulmonary hypertension (as manifestations of nonhepatosplenic 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 suitable for the group of patients with intermediate-2 risk (DIPSS Plus - 2-3 points) or high risk (4 or more points on DIPSS Plus).

One of traditional methods is the treatment of symptomatic anemia. In a small proportion 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 the 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

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

More traditional treatment for anemia in PMF is androgens (for example, testosterone enanthate* 400-600 mg intramuscularly once a week, fluoxymesterone* 10 mg 2-3 times a day orally or danazol 600 mg/day orally) and prednisolone (0.5 mg/kg per day). Androgens are commonly used for anemia with low reticulocyte counts and failure of prednisone therapy. Patients with chromosomal abnormalities are less sensitive to androgen treatment. Prednisolone per os also used for treatment 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%, response duration is 1-2 years. It should be noted that lenalidomide is most effective in the presence of del(5q): during therapy, these patients are shown to achieve complete remission, so detection of 5q in patients can serve as a basis for differentiated early administration of this drug in the presence of symptoms of PMF. Another modern derivative of thalidomide*, the drug pomalidomide*, is also effective for anemia, but mainly in JAK2V617F-positive patients with severe splenomegaly. Main side effects: hepatotoxicity and virilizing effects in androgens, peripheral neuropathy in thalidomide* and myelosuppression (neutropenia and thrombocytopenia) in lenalidomide, tendency to thrombosis (concomitant administration of acetylsalicylic acid is indicated). Thalidomide* and Lena-lidomide are contraindicated in women of childbearing age. Glucocorticoids should be avoided in case of diabetes and osteoporosis, and androgens or danazol in case of increased levels of prostate-specific antigen or a history of prostate cancer. Transfusions of red blood cells are indicated for patients with clinical manifestations of anemic syndrome in order to maintain hemoglobin levels at a level at which symptoms caused by anemia disappear. Cyclosporine A may also be used to treat transfusion-dependent anemia in patients with PMF.

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

ICD-10 code

C94.5 Acute myelofibrosis

Epidemiology

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

Causes of myelofibrosis

Myelofibrosis is characterized by fibrotic degeneration of the bone marrow with 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 primary disease, which is likely due to neoplastic transformation of multipotent bone marrow stem cells - these stem cells stimulate bone marrow fibroblasts (this process is not part of neoplastic transformation) to advanced education collagen. Myelofibrosis can also occur due to various hematological, oncological and infectious diseases. In addition, myelofibrosis may be a complication chronic myeloid leukemia and occurs in 15-30% of patients with polycythemia vera and long course diseases. A large number of immature red blood cells and granulocytes enter the bloodstream (leukoerythroblastosis), which may be accompanied by increased activity Blood LDH. Myelofibrosis results in failure of bone marrow hematopoiesis 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 in fact a true megakaryocytic leukemia.

Conditions associated with myelofibrosis

Symptoms of myelofibrosis

The early stages may be asymptomatic. Splenomegaly may occur; for more late stages patients may complain of general malaise, weight loss, fever, and splenic infarctions may be detected. 50% of patients have hepatomegaly. Sometimes lymphadenopathy is detected, but this symptom is atypical 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 unexplained elevated LDH levels. If the disease is suspected, it is necessary to perform a general clinical blood test and conduct a morphological study of peripheral blood and bone marrow with cytogenetic analysis. It is necessary to exclude other diseases associated with myelofibrosis (for example, 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 characteristic feature disease and tends to progress. The erythrocytes are normochromic-normocytic with slight poikilocytosis; in addition, reticulocytosis and polychromatophilia are observed. Nucleated red blood cells may be found in peripheral blood. In the later stages of the disease, red blood cells are deformed and may have the shape of a drop; These changes are quite enough to suspect this disease.

The white blood cell count is usually elevated but very variable. As a rule, immature neitrophils 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 low; As the disease progresses, there is a tendency towards thrombocytopenia. Levels of progenitor cells may increase in the peripheral blood (as detected by counting CD34+ cells).

Bone marrow aspirate is usually dry. Since bone marrow fibrosis must be detected to confirm the diagnosis, and fibrosis may be unevenly distributed, if the first biopsy is uninformative, it must be repeated elsewhere.

05.10.2017

Myelofibrosis (myeloproliferative disease) is characterized by: anemia of varying intensity, various changes in peripheral blood, myeloid metaplasia of the spleen and organs, and marrow (bone) fibrosis. The pathology occurs due to a mutated clone, which originates in a hematopoietic stem cell. Treatment of myelofibrosis is aimed at alleviating the patient’s condition and reducing symptoms. If the diagnosis is confirmed, the patient is given disability.

Initial stage of myelofibrosis

Symptoms and manifestations

There may be no symptoms of myelofibrosis; patients become aware of the presence of the disease during pathology examinations. This is because myelofibrosis is a disease that progresses slowly. This pathology does not have a pronounced division according to the sign. There is an age dependence - it occurs in people old age, detections are rare among young people.
The disease produces symptomatic manifestations in the later stages and they are expressed by the standard disturbances of well-being for anemia:

causeless weakness;
constant drowsiness;
excessive fatigue;
dyspnea.

Since pathology can provoke an increase in the size of the spleen, symptomatic manifestations have a relationship with the organ:

negative feelings while eating food;
heartburn and bloating;
swelling of the legs below the kneecap.

The altered spleen reaches large parameters and takes up space in the peritoneum. This causes a splenic infarction; the main signs are sharp pain on the left and sensations of friction of the peritoneum.

Myelofibrosis can also cause a number of general manifestations:

Feel severe itching(more often - in the warmth);
bone soreness;
calf muscle cramps;
signs of gout.

The disease may cause gastrointestinal and capillary bleeding, and idiopathic myelofibrosis provokes local osteosclerosis in 30% of cases.

Causes

Primary myelofibrosis is more common than secondary myelofibrosis. It develops due to malignancy of pluripotent stem cells in the bone marrow. These cells enhance the production of collagen at the expense of BM fibroblasts (they do not take part during malignancy).

In the primary form of the pathology, a significant number of nucleated normoblasts (erythrocytes) with leukoerythroblasts (granulocytes) are released. The content of LDH in the blood plasma increases. CM deficiency occurs with progression of thrombocytopenia and anemia. Acute leukemia, not amenable to chemotherapy, occurs in 10% of cases.

The causes of primary myelofibrosis are unknown, but the secondary form of the pathology occurs due to a disease that affects the bone marrow. VM can be triggered by:

cancer metastases;
polycythemia;
HIV infection;
lymphoma;
chronic leukemia or acute leukemia;
multiple myeloma.

The pathological process can begin under the influence of a number of toxins (benzenes) or radiation (X-rays).

Myelofibrosis is characterized by disorders:

bone marrow fibrosis;
leuko-erythroblastic blood picture;
extramedullary hematopoiesis.

At the initial stage, an overestimation of pathological megakaryocytes is observed. They produce growth factors, provoking the proliferation of fibroblasts.

Diagnosis

To identify pathology they are used lab tests And clinical researches. A blood test is key. When it confirms the presence of nucleated cells of the erythrocyte group and young granulocytes, the diagnosis is considered true.

Anemia may occur in primary myelofibrosis

The presence of the disease is confirmed by increased concentration uric acid. The number of leukocytes (white blood cells) increases greatly. Cellular metabolic processes blood changes, which causes a lack of water-soluble vitamin B9. There is a lack of iron, which is caused by bleeding in the digestive system and changes in the size of the spleen.

Specialists do not perform a bone marrow puncture to confirm the disease - all tests were inaccurate and the result was erroneous. This is caused by scar tissue that prevents the collection of material for execution. this study. However, trepanobiopsy of the formative pelvic bone makes it possible to identify pathology with a high degree of probability, since it is the largest of the 3 pairs.
The main studies that a patient undergoes if a pathology is suspected are as follows:

histological examination of bone marrow;
cytogenetic study of bone marrow;
cytological examination of bone marrow;
CT or ultrasound of the abdominal cavity.

High reliability was shown by the study of tissues by impregnation using a solution of silver nitrate - it makes it possible to determine the concentration of reticuline. Depending on the results of the studies and tests performed, the stage of the disease is determined.

Stages of pathology

According to the classification, myelofibrosis is divided into 6 types, determined by symptomatic manifestations:

thrombocytomic;
classical;
anemic without reticulosis;
erythremic;
anemic with reticulosis;
thrombocytopenic.

The course of myelofibrosis is divided into three phases:

Early, otherwise – proliferative.
Fibrotic-sclerotic.
The phase in which acute leukemia is observed, otherwise known as the blast phase.

The progression of the disease is established as a result of studies of the size of the spleen. A significant role is played by the development of symptoms of anemia.

The first and second phases are chronic and are caused by a slow worsening of leukocytosis. According to data, only 15% of patients suffer from the transition of pathology to acute (secondary) leukemia, which is an incurable disease.

Treatment of myelofibrosis

Treatment tactics that would reverse the disease have not yet been developed. For this reason, methods are selected according to the individual picture by a hematology specialist. Treatment of primary myelofibrosis is aimed at alleviating symptomatic manifestations, accompanying pathologies complications. Initiation of therapy guarantees a slowdown pathological process and forecast.

Treatment begins with therapy aimed at restoring the spleen and bringing hemoglobin concentrations to physiological norm. The following palliative measures are used:

androgens;
splenic embolization;
chemotherapy;
radiation therapy.

Methods traditional treatment do not lead to improvement in the patient’s condition – they are used complex techniques. There are cases of using allogeneic stem cell transplantation without the use of BM ablation among people in the older age group. It is performed on patients under 65 years of age. When treatment doesn't work positive results, and the patient's condition worsens, apply radical method – surgical intervention to remove the spleen.

Predictions and prevention

If the patient's condition worsens and progressive anemia combined with splenomegaly, the prognosis is unfavorable - the patient's life expectancy is no more than 3 years. 1/5 of all cases of myelofibrosis are completed fatal due to the development of acute leukemia. When hemoglobin levels can be stabilized and brought back to normal, the prognosis is favorable - the patient will live a long time.

Myelofibrosis is a disease of the bone marrow that can lead to death. For this reason, after confirmation of the oncological process, the patient is given disability. The group is determined by the severity of the person's condition. On initial pathology, when there is no reliable information on the diagnosis, disability is not given.

Due to insufficient knowledge of the mechanisms of myelofibrosis, no specific preventive measures not developed. The main prevention is to follow the basics of a healthy lifestyle, preventive examinations for early diagnosis.

Description:

Myelofibrosis (myelofibrosis) is a myeloproliferative disease, which is characterized by varying severity - from moderate to severe, very diverse changes in the peripheral blood, bone marrow fibrosis and myeloid metaplasia of the spleen, liver and other organs.

Symptoms:

Myelofibrosis can occur against the background of true or thrombocythemia, but it usually develops as 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. Persons of both sexes get sick equally often.

The disease progresses slowly, and due to its hidden onset, the diagnosis is often made when examining a patient for a completely different reason. Symptoms caused by anemia are often observed: drowsiness, weakness, and physical activity. Sometimes the first manifestations of the disease are symptoms caused by an enlarged spleen, namely bloating, a feeling of discomfort after eating, and even in the ankle area. Splenomegaly - almost constant sign, the spleen in some cases is slightly enlarged, in others it reaches enormous sizes, actually occupying the entire abdominal cavity. Splenic infarction is accompanied by acute pain in the left hypochondrium and peritoneal friction noise. Hepatomegaly is often detected. occurs as a result of the splenic vein, the formation of extramedullary infiltrates of proliferating cells along the portal tract or its increased blood supply. In patients with portal hypertension may arise , and .

Signs are often found. Patients also suffer from itching, which becomes especially painful in warm weather. Occur in calf muscles, bone pain, and all these symptoms can very easily be attributed to the patient’s age.

Occasional functional disorders platelets are the cause of intradermal hemorrhages and gastrointestinal bleeding. Approximately 1/3 of patients with myelofibrosis have focal osteosclerosis, usually involving the bones of the axial skeleton and the proximal epiphyses of the humerus and femur. Rarely, other areas of the skeleton, such as the skull, are affected.

Course and prognosis

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 moment of diagnosis is 3 years, but many patients live longer. Unfavorable prognostic signs are severe anemia, which cannot be eliminated with blood transfusions, severe, spontaneous bleeding and quick loss body weight. All of these symptoms may be due to a deficiency folic acid. The cause of death is most often progressive anemia; approximately 20% of patients die from acute myeloblastic.

Causes:

The disease occurs as a result of the proliferation of a mutant clone originating from a hematopoietic stem cell that is capable of differentiating towards erythrocytes, granulocytes and platelets. Proliferation of osteoblasts and formation of new tissue are also often observed. bone tissue. It is unknown whether bone marrow fibrosis is a response to disturbances in cell proliferative activity hematopoietic system or a component of such pathological proliferative reactions. Myeloid metaplasia of the spleen, liver and other organs is usually considered as compensatory process; it is possible, however, that it is the result of stem cell proliferation.

Treatment:

For treatment the following is prescribed:

Specific treatment No. Patients with moderate symptoms require only periodic examination. Anemia is the main reason for starting therapy. Often folate deficiency can be treated well with folic acid. Myelofibrosis is one of the few diseases for which long-term preventive intake of folic acid at a dose of 5 mg/day is indicated. You should make sure that the patient does not have impaired absorption of vitamin B12. Many patients are prescribed androgens, but the latter are not always effective; if the condition improves, it is 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 a level of 90-100 g/l. However, before starting a repeat transfusion program, you should carefully evaluate general state patient. Afterwards, the rise in hemoglobin levels is often less than expected, and ultimately its increase becomes smaller in magnitude and shorter in time, and the improvement lasts only 1-2 weeks. This may be due to the destruction of transfused red blood cells in the spleen.

Deposition of blood in the spleen is important reason development of anemia, the degree of deposition must be determined using 51Cr. Very effective means Myelosan reduces the size of the spleen - a short course of treatment with this drug leads to long-term improvement in the patient’s condition.

To reduce the size of the spleen, 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 counts. The safer method of embolization is through an intra-arterial catheter.

What is Myelofibrosis
What causes Myelofibrosis?
Symptoms of Myelofibrosis
Diagnosis of Myelofibrosis
Treatment of Myelofibrosis
Prevention of Myelofibrosis
Which doctors should you contact if you have Myelofibrosis?

What is Myelofibrosis

Myelofibrosis (myelofibrosis) is a myeloproliferative disease characterized by anemia of varying severity - from moderate to severe, very diverse changes in the 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 red blood cells, granulocytes and platelets. Proliferation of osteoblasts and formation of new bone tissue are also often observed. It is unknown whether bone marrow fibrosis is a reaction to disturbances in the proliferative activity of cells of the hematopoietic system or a component of such pathological proliferative reactions. Myeloid metaplasia of the spleen, liver and other organs is usually considered a compensatory process; it is possible, however, that it is the result of stem cell proliferation.

What causes Myelofibrosis?

Pathogenesis (what happens?) during Myelofibrosis

Symptoms of Myelofibrosis

Myelofibrosis can occur due to polycythemia vera or thrombocythemia, but it usually 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 the age group of 50-70 years. Persons of both sexes get sick equally often.

The disease progresses slowly, and due to its hidden onset, the diagnosis is often made when examining a patient for a completely different reason. Symptoms associated with anemia are often observed: drowsiness, weakness and shortness of breath during exercise. 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 is an almost constant symptom; in some cases the spleen is slightly enlarged, in others it reaches enormous sizes, actually occupying the entire abdominal cavity. Splenic infarction is accompanied by acute pain in the left hypochondrium and peritoneal friction noise. Hepatomegaly is often detected. Portal hypertension occurs as a result of 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 esophageal veins and ascites.

Signs of gout are often found. Patients also suffer from itching, which becomes especially painful in warm weather. Cramps in the calf muscles and pain in the bones occur, and all these symptoms can very easily be attributed to the patient’s age.

Functional platelet disorders that sometimes occur cause intradermal hemorrhages and gastrointestinal bleeding. Approximately 1/3 of patients with myelofibrosis have focal osteosclerosis, usually involving the bones of the axial skeleton and the proximal epiphyses of the humerus and femur. Rarely, other areas of the skeleton, such as the skull, are affected.

Course and prognosis

The condition of many patients remains stable for many years with normal hemoglobin levels and minimal splenomegaly. In some patients, the disease is less benign, characterized by a gradual deterioration in health, progression of anemia and splenomegaly. The average lifespan from diagnosis is 3 years, but many patients live longer. Poor prognostic signs include severe anemia that cannot be corrected by blood transfusions, severe leukopenia, spontaneous bleeding, and rapid weight loss. 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.

Diagnosis of Myelofibrosis

By the time you apply for medical care anemia is found in 2/3 of all patients. Being weakly or moderately expressed on early stages The disease becomes more severe as it progresses. Polychromasia, anisocytosis, poikilocytosis are noted, and teardrop-shaped cells appear. Nucleated erythrocytes and immature granulocytes are often found in peripheral blood. Folic acid deficiency often occurs due to insufficient dietary intake and increased blood cell turnover. In case of blood loss, iron deficiency occurs. The number of leukocytes is often increased, they are represented mainly by mature leukocytes, and immature forms are also usually found.

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

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

Blood uric acid levels are usually high in myelofibrosis.

Treatment of Myelofibrosis

There is no specific treatment. Patients with moderate symptoms require only periodic examination. Anemia is the main reason for starting therapy. Often folate deficiency can be treated well with folic acid. Myelofibrosis is one of the few diseases for which long-term preventive intake of folic acid at a dose of 5 mg/day is indicated. You should make sure that the patient does not have impaired absorption of vitamin B12. Many patients are prescribed androgens, but the latter are not always effective; if the condition improves, it is only after a few weeks.

If the anemia is so severe that it causes cardiovascular disorders, then it is necessary to give blood transfusions, trying to maintain hemoglobin at a level of 90-100 g/l. However, before starting a repeat transfusion program, the patient's general condition should be carefully assessed. After a blood transfusion, the rise in hemoglobin levels is often less than expected, and ultimately the increase becomes smaller in magnitude and shorter in duration, with improvement lasting only 1-2 weeks. This may be due to the destruction of transfused red blood cells in the spleen.

Blood deposition in the spleen is an important cause of anemia; the degree of deposition must be determined using 51 Cr. Myelosan is a very effective means of reducing the size of the spleen - a short course of treatment with this drug leads to a long-term improvement in the patient’s condition.