Myelofibrosis is a chronic hematological disease characterized by tumor proliferation of hematopoietic stem cells and bone marrow fibrosis. The main clinical manifestations include symptoms of tumor intoxication and anemic syndrome (progressive weakness, pallor of the skin and mucous membranes, weight loss), as well as enlargement of the spleen (splenomegaly). The diagnosis is established on the basis of molecular genetic studies, the study of the histological picture of the bone marrow. Treatment is carried out with the help of chemotherapeutic drugs. Surgical methods of treatment involve bone marrow transplantation and removal of the spleen.
ICD 10
C94.4 Acute panmyelosis
Meaning
Myelofibrosis (agnogenic myeloid metaplasia, subleukemic myelosis) is a malignant disease in which the bone marrow is gradually replaced by tumor stem cells and growing connective tissue. For the first time this pathology was described by the German physician G. Hoik in 1879. And in 1951, the American hematologist William Dameshek myelofibrosis was isolated into an independent nosological unit. With an unfavorable course, myelofibrosis can transform into a more serious disease ‒ acute leukemia. The prevalence of myelofibrosis ranges from 0.3 to 0.7 cases per 100 thousand population. The peak incidence occurs at the age of 50 to 70 years, but there are also young patients. Men suffer more often.
Myelofibrosis causes
There is primary and secondary subleukemic myelosis. The exact cause of primary myelofibrosis has not yet been established. The theory of the influence of genetic mutation is the most popular among specialists in the field of hematology. Mutations of tyrosine kinase (JAK2V617F), calreticulin (CALR), and thrombopoietin (MPL) genes regulating the expression of JAK-STAT signaling pathway proteins are detected in most patients. The genes are localized at the del3p24 chromosome locus.
The effect of a large dose of radioactive radiation is studied as an etiological factor. The role of persistent viral infections (herpes simplex virus, Epstein-Barr, cytomegalovirus), prolonged use of oral contraceptives, myelosuppressive medications, contact with various organic and inorganic compounds (benzene, arsenic) is also considered. Secondary myelofibrosis develops as an outcome of other chronic myeloproliferative diseases – true polycythemia, essential thrombocytemia, chronic myeloid leukemia.
Pathogenesis
As a result of increased expression of signaling proteins, active proliferation (tumor transformation) is triggered in one of the bone marrow stem cells. This process is accompanied by secondary inflammation with the release of cytokines and growth factors. Fibroblast and vascular endothelial growth factors induce the production of large amounts of collagen by bone marrow stromal cells and the proliferation of connective tissue (fibrosis proper). Gradually, the normal bone marrow tissue is replaced by a tumor and connective tissue.
With a massive lesion of the bone marrow tumor, blood cells, before reaching the stage of full maturation, enter the systemic circulation. This leads to the formation of foci of extramedullary (extra-medullary) hematopoiesis, mainly in the liver and spleen. The collapse of the tumor leads to the release of uric acid, which is deposited in the tissues of the joints and renal tubules.
Myelofibrosis symptoms
The patient feels satisfactory for a long time. A few years after the onset of the disease, tumor intoxication gradually appears in the form of general weakness, an increase in temperature to subfebrile figures, sweating, which increases at night. The patient’s appetite decreases, he rapidly loses weight. Anemic syndrome joins (pallor of the skin, dizziness, palpitation of the heart). Nasal, gingival bleeding, hemorrhagic rashes on the skin are characteristic. There are joint pains, skin itching, bone pain.
The patient feels heaviness and pain in the left hypochondrium due to a pronounced enlargement of the spleen. Against the background of splenomegaly, hypersplenism syndrome develops, which consists in the massive destruction of blood cells (mainly erythrocytes) in the sinusoids of the spleen. In this case, there are signs of hemolysis (jaundice of the skin, mucous membranes, darkening of urine).
Rare symptoms are associated with unusual localization of foci of extramedullary hematopoiesis – in the lungs (cough, difficulty breathing, hemoptysis), gastrointestinal tract (abdominal pain, bloody diarrhea). When foci are located in the central and peripheral nervous system, epileptic seizures, sensitivity disorders, weakness of movements in the extremities, up to complete paralysis are observed.
Complications
With myelofibrosis, blood clots often form, which lead to acute cerebrovascular accident, myocardial infarction, pulmonary embolism. A persistent decrease in the level of leukocytes is often associated with various infections that acquire a severe course. The most unfavorable complication is the transformation of myelofibrosis into myeloid leukemia (blast crisis), which is difficult to treat. Atypical complications include pathological fractures due to the destruction of tubular bones and portal hypertension, which is caused by prolonged obstruction of intrahepatic veins by microthrombs.
Diagnostics
Hematologists are responsible for the curation of patients with myelofibrosis. During a general examination, attention is drawn to the discoloration of the skin, mucous membranes (pallor or jaundice), splenomegaly with palpation and percussion of the spleen, sometimes reaching gigantic sizes (up to the pubic symphysis). Additional diagnostic methods include:
- Laboratory test. At the beginning of the disease, an increase in erythrocytes, platelets, and leukocytes is detected in the general blood test, which eventually changes to low values. Often immature forms of erythrocytes, leukocytes (myelocytes, promyelocytes) are present in peripheral blood. In the biochemical analysis of blood, elevated concentrations of lactate dehydrogenase (LDH), ionized calcium are observed. There are changes in the coagulogram – acceleration of blood clotting, reduction of activated partial thromboplastin time, inhibition of fibrinolysis processes. In the analysis of urine, urobilin, hemoglobin, urates (uric acid salts) are detected.
- Bone marrow examination. A bone marrow sample is obtained by trepanobiopsy. The histological picture depends on the phase of the disease. The early (prefibrotic phase) is characterized by hyperplasia of all hematopoietic sprouts (granulocytic, megakaryocytic, erythroid) with immaturity of cells. In the late (fibrotic) phase, a large number of collagen and reticular fibers (fibrosis) replacing hematopoietic tissue, pronounced cellular atypia is determined. A high level of blast cells (more than 20%) indicates the transformation of myelofibrosis into acute leukemia.
- Molecular genetic tests. Diagnosis of mutations of the JAK2V617F, CALR, MPL genes is carried out by the FISH method. A real-time polymerase chain reaction is performed to identify the allelic load of the mutation. HLA typing is also performed to address the possibility of bone marrow transplantation.
- Cytogenetic and cytochemical analyses. During cytogenetic examination (karyotyping) of bone marrow cells, abnormalities of 1, 3, 6 chromosomes (translocation, trisomy, complex disorders) are found. When analyzing the chemical composition (cytochemistry) of neutrophils, the activity of alkaline phosphatase is 3 times higher than normal.
Special criteria have been developed for reliable diagnosis by the hematology community. Large criteria include increased bone marrow cellularity with reticular and collagen fibrosis, the presence of mutations of the JAK2V617F, MPL, and CALR genes. Small criteria include anemia, splenomegaly, leukoerythroblastosis (the presence of immature forms of leukocytes, erythrocytes in the blood), as well as an increase in lactate dehydrogenase. The diagnosis is considered confirmed if there are 2 large criteria or 1 large and 3 small criteria.
Myelofibrosis should be differentiated primarily with hematological diseases, such as autoimmune hemolytic anemia, hemoblastosis (leukemia, lymphoma). The combination of splenomegaly with symptoms of intoxication (weakness, subfebrility, night sweating) requires the exclusion of tuberculosis, subacute infectious endocarditis.
Myelofibrosis treatment
After the diagnosis, the patient should be hospitalized in a hematology hospital. To make a decision on the choice of treatment tactics, it is necessary to determine the degree of risk, namely, the probability of blast transformation and approximate life expectancy. For this purpose, the “International Risk Assessment and Forecast Scale” (DIPSS) was created. It takes into account the age of the patient, the number of shaped blood elements, the severity of symptoms of tumor intoxication. Each attribute corresponds to one point. There are low, first and second intermediate, high risks at which differentiated therapy is carried out:
- Medical treatment. At low and 1st intermediate risk, glucocorticosteroids (prednisone, dexamethasone), erythropoietin, alpha-interferon are used. In severe cachexia, anabolic steroids (retabolil) are used. In some cases, they resort to transfusion of blood components (plasma, erythrocyte mass, thromboconcentrate).
- Surgical methods. For patients with the 2nd intermediate and high risk therapy of choice is bone marrow transplantation. This operation allows to achieve complete remission of the disease. With a significant increase in the spleen, causing compression of neighboring organs with portal hypertension, its removal (splenectomy) is indicated.
- Targeted therapy. If it is impossible to perform TCM, targeted (targeted) pathogenetic therapy with JAK kinase inhibitors, which act on a key link in pathogenesis (intracellular signaling pathway), is prescribed. To date, only one drug from this group has been registered in the Russian Federation – ruxolitinib.
- Chemotherapy. With myelofibrosis, chemotherapy with cytostatics (hydroxyurea, mercaptopurine, cytarabine), gamma irradiation of foci of extramedullary hematopoiesis is also performed. With blast transformation, they switch to the standard chemotherapeutic protocol for acute leukemia.
Prognosis and prevention
Myelofibrosis is a serious disease with an unfavorable prognosis. From the moment of diagnosis, the average life expectancy is about 5 years. When manifested at a younger age, myelofibrosis has a less aggressive course, which is associated with a better response to therapy and greater survival of patients. Effective methods of prevention have not been developed due to the unknown etiological factor. Prevention of the development of secondary myelofibrosis consists in the timely diagnosis and treatment of pathologies against which it occurs – true polycythemia and essential thrombocytemia.
Literature
- Agrawal M., Gard R.J., Cortes J. et al. Experemental therapeutics for patients with myeloproliferative neoplasias. Cancer 2011;117(4):662-76. link
- Baxter E.G., Scot L.M., Campbell P.J. et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 2005;365(9464):1054-61.
- Bench A.J., Nacheva E.P., Champion K.M., Green A.M. Molecular genetics and cytogenetics of myeloproliferative disorders. Baillieres Clin Haematol 1998;11:819-48. link
- Bornhauser M., Mohr. B., Oelschlaegel U. et al. Concurrent JAK2V617F mutation and BCR-ABL translocation within commited myeloid progenitors in myelofibrosis. Leukemia 2007;21(8):1824-6. link
- Kralovics R., Passmonti F., Busser A.S. et al. Again-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med 2005;352:1779-90.
- Levine R.L., Wadleigh M., Cools J., Wlodarska I. et al. Activating mutation in the tyrosin kinase JAK2 in polycythemia vera, essential trombocythemia and myeloid metaplasia with myelofibrosis. Cancer Cell 2005;7(4):387-97. link
- Reilly J.T., Snowden J.A., Spearing R.L. et al. Cytogenetic abnormalities and their prognostic significance in idiopathic myelofibrosis: a study of 106 cases. Br J Haematol 1997;98:96-102.