Secondary changes in the bone marrow. Clinical presentation and treatment of myelodysplastic syndrome

MYELODYSPLASTIC SYNDROMES:

mechanisms of development, symptoms, treatment

What is MDS?

Myelodysplastic syndromes (MDS) are a group of diseases with primary bone marrow involvement, where the bone marrow does not produce enough healthy blood cells.

Myelodysplastic syndromes mainly affect the elderly (the majority of patients are between 60 and 85 years old), but younger people (from 30 years old) can also get sick with myelodysplastic syndromes.By type, MDS differ in primary (idiopathic) - 80-90% of cases, secondary (due to previous chemotherapy and other factors) - 10-20%. Sporadic, hereditary - rarely occur, but in this case Fanconi's anemia or other variants of the phenotype with mutator genes must be excluded. The 5-year survival rate for MDS does not exceed 60%.

With a few exceptions, the cause of MDS is unknown. Some people have had congenital MDS. If such external factor it is impossible to establish, the disease is called "primary MDS".

Risk factors for primary MDS are considered contact with toxins (gasoline, organic solvents, pesticides), ionizing radiation, smoking, congenital and hereditary diseases (Fanconi anemia, severe congenital neutropenia, Schwachman-Diamond syndrome, Diamond-Blackfan anemia), elderly age... Secondary MDS may develop after prior chemotherapy cancer (Hodgkin's lymphoma, breast cancer, etc.) or after blood cell transplantation as a result of mutagenic effects of a number of drugs (mechlorethamine, procarbazine, chlorambucil, etc.).

There is no convincing evidence that MDS can cause any viruses, so MDS cannot be transmitted to people around. Since family members are not at high risk, they should not undergo additional testing.

MDS develops as a result of a disruption in the normal function of the bone marrow.

The main function of the bone marrow is the production of blood cells, which include red blood cells, platelets and white blood cells. Each of these cells, after leaving the bone marrow, performs important life-saving functions. The provision of tissues and organs with oxygen (erythrocytes), stopping bleeding (platelets) and protection against infections (leukocytes) depend on them. Healthy bone marrow contains immature blood cells called stem cells or progenitor cells, which are converted as needed into mature red blood cells, white blood cells, and platelets to perform their functions.

In MDS, these stem cells may not reach maturity and / or have a shortened life cycle, dying in the bone marrow before they enter the bloodstream, which leads to a decrease in the number of mature circulating blood cells (called cytopenia) and, accordingly, to a decrease in their function. In addition, mature blood cells circulating in peripheral blood, can malfunction due to the so-called dysplasia - abnormalities in the shape or morphology of blood cells in the bone marrow and / or peripheral blood.

The inability of the bone marrow to produce healthy mature cells occurs gradually, and therefore patients can suffer long-term consequences of the disease, such as anemia, bleeding and reduced resistance to infection. In addition, 30% of MDS patients may develop acute myeloid leukemia (AML).

Clinical manifestations of MDS

Many patients in the early stages of the disease do not experience any symptoms. there are enough mature cells in the blood. One of the most characteristic symptoms at the onset of the disease is anemia (decreased number of erythrocytes, hemoglobin and hematocrit).

Patients suffering from anemia usually experience a constant feeling of fatigue, weakness, decreased performance, inability to concentrate. Women tolerate anemia better than men. As anemia grows, increased heart rate, difficulty breathing, drowsiness, dizziness join. Fainting may develop. Anemia is especially difficult for elderly patients and people with diseases of the heart and lungs: they may develop angina pectoris (pain in the region of the heart), myocardial infarction, increase shortness of breath, decrease tolerance physical activity, cardiac arrhythmias may develop.

With the defeat of the vessels of the lower extremities, the manifestations of the so-called intermittent claudication (the appearance of pain in the legs when walking over short distances) intensify. Therefore, it is often found out about changes in blood tests during examination for therapeutic pathology..

Often, patients undergo anemia treatment under the supervision of a therapist who uses iron supplements, vitamin B12, folic acid for this purpose, but does not achieve success, i.e. anemia is "refractory" (resistant) to these commonly used drugs, which may lead to consultation with a hematologist.

Anemia can be accompanied by a decrease in the number of neutrophils (neutropenia) and platelets (thrombocytopenia). A low number of leukocytes in the blood (the norm is from 4000 to 10000 leukocytes in 1 microliter of blood) reduces the body's resistance, primarily to bacterial infection. Patients often suffer from recurrent skin infections, infections of the ear, throat and nose, broncho-pulmonary infections (bronchitis, pneumonia) and infections of the urinary tract, oral cavity (stomatitis) and teeth, accompanied by fever.

With thrombocytopenia (normal blood count is from 130,000 to 450,000 platelets in 1 microliter of blood), patients have increased bleeding with a tendency to bruise and bleeding even as a result of minor bumps and scratches. Even small cuts may take longer than usual to stop bleeding. Severe thrombocytopenia, which is observed in rare cases, occurs when the number of platelets decreases below 20,000 in 1 μl or 20x10 9 / l and is accompanied by bleeding.

The bruising can be significant, some as large as the palm of your hand. Nosebleeds are common and patients complain of bleeding gums, for example, during dental procedures, and women may have more heavy menstrual bleeding.

A patient with MDS is advised to consult a hematologist before seeking dental care, given the risk of bleeding and infection. Moreover, according to indications, medications can be prescribed (prophylactic antibiotics, etc.).

Diagnosis of MDS

1. The first step in diagnosing MDS is a CBC by taking a blood sample from a vein. The blood sample determines the number of blood cells (erythrocytes, leukocytes and their subtypes, as well as platelets), the shape and size of erythrocytes and leukocytes.

2. To exclude the most common anemias, a blood serum test is performed, which determines the level of iron and ferritin (assessment of iron stores in the body), vitamin B 12 and folic acid, erythropoietin (a protein that is produced in the kidneys in response to low oxygen levels in body tissues, stimulates the formation of red blood cells in the bone marrow).

3. If the cause of the bone marrow lesion is considered probable, a bone marrow examination is indicated. Bone marrow examination includes a study of a bone marrow aspirate (myelogram analysis, cytological examination) obtained by taking a sample of liquid bone marrow, and a bone marrow trepanobiopsy (a sample of the bone component of the bone marrow).

In the process of bone marrow examination, the following are determined:

1) the percentage of blasts and cells with signs of dysplasia;

3) chromosomal abnormalities, such as missing or extra chromosomes in bone marrow cells. Any abnormalities are reported on the hematology report, and chromosomal abnormalities (missing or deleted chromosomes, and altered or extra chromosomes or parts of chromosomes) are reported on the cytogenetic test. Subsequently, repeated bone marrow examinations are performed in MDS patients in order to determine the clinical status of MDS over time (remission, stabilization, progression) and to assess the effect of the therapy.

Determination of the severity of MDS in humans.

Based on the information received, not only the diagnosis of MDS is established, but also the subtype of the disease and the prognosis of the course in a particular patient are determined. For this, various classification systems have been developed. According to the latest proposed classification, known as the World Health Organization (WHO) Classification, there are six different subtypes of MDS, the separation of which is based on analysis of large international databases and on a better understanding of disease progression.

In the past, the French-American-British classification system (FAB classification) was widely used. Some hematologists continue to use this system today.

FAB classification was developed in the early 1980s by a group of doctors from France, the United States of America and the United Kingdom who specialized in the diagnosis of MDS. The main criterion in this classification was the percentage of blast cells in the bone marrow, while the percentage of these cells less than 2% was considered normal for healthy bone marrow. According to the FAB classification, the following five subtypes of MDS are distinguished:

· refractory anemia (RA);

· refractory anemia with annular sideroblasts (RAKS);

· refractory anemia with excess blasts (RAEB);

· refractory anemia with excess blasts in transformation (RAEB-T);

· chronic myelomonocytic leukemia (CML).

The WHO classification system for MDS in adults retains some elements of the FAB classification system and expands the categories of MDS subtypes. The main characteristics of the six subtypes of MDS, distinguished by the WHO classification system, are highlighted in the table below.

Noteworthy changes in the WHO classification system compared to the FAB classification system are as follows:

· division of the RAIB subtype into two subtypes;

· exclusion of HMML as an independent subtype;

· inclusion of MDS with chromosomal abnormality "syndrome 5q - "as a separate subtype;

· exclusion of the subtype refractory anemia with excess blasts in transformation (RAEB-T), which is currently considered to be included in AML;

· introduction of the category "MDS unclassified".

Refractory anemia (RA). Patients in this category suffer from anemia that does not respond to treatment with iron or vitamins, that is, is refractory to such treatment. Anemia can be associated with mild to moderate thrombocytopenia and neutropenia.

Refractory anemia with annular sideroblasts (RAKS).In patients with this type of anemia, dysplasia is noted only in the erythroid row. Sideroblasts are erythroid cells containing iron granules; annular sideroblasts are abnormal. Refractory anemia with or without annular sideroblasts (RARS) is considered the most benign subtype in the WHO classification system.

Refractory cytopenia with multilinear dysplasia (RCMD). This category includes patients with refractory cytopenia (persistent low blood cell count of some type, such as refractory neutropenia or refractory thrombocytopenia) and who have minimal dysplasia in at least two types of blood cells, and a blast count of 5% and less, or the number of annular sideroblasts is less than 15%. If the number of annular sideroblasts in a patient with RCMD exceeds 15%, a diagnosis of RCMD-CS is made.

WHO-classification of MDS
MDS subtype	Characteristic
RA	Minimal dysplasia in one type of blood cell (red blood cells or red blood cells) and< 5% бластов в костном мозге
RAKS	Dysplasia of erythroid lineage only and\u003e 15% annular sideroblasts
RCMD	Dysplasia (\u003e 10%) in two or three types of blood cells< 5% бластов и < 15% кольцевых сидеробластов в костном мозге (количество кольцевых сидеробластов > 15% is called RCMD-KS)
RAIB
RAIB 1	The number of blasts in the bone marrow is from 5% to 9%
RAIB 2	The number of blasts in the bone marrow is from 10% to 19%
MDS / MPZ	Dysplasia in the presence of characteristics usually associated with myeloproliferative disease; includes HMML
Syndrome 5q-	Patients who do not have chromosomal abnormalities, with the exception of a deletion in the long arm of chromosome 5
MDS unclassified	Includes patients with cytopenia in one type of blood cell other than anemia (ie, neutropenia or thrombopenia) and any unusual characteristics (eg, bone marrow fibrosis)

Refractory anemia with excess blasts (RAEB). This category is divided into two subcategories, which differ in the number of blasts in the bone marrow. In patients with RAEB-1, the number of blasts ranges from 5% to 9%, and in patients with RAEB-2, from 10% to 19%.

Myelodysplastic Syndrome / Myeloproliferative Disease (MDS / MPD). Patients with MDS / MPD include those with chronic myelomonocytic leukemia (CML), which is a separate category in the FAB classification system.

5 q- (5 q minus) syndrome. 5 q syndrome -, currently classified as a separate subtype of MDS, was first described more than 30 years ago. The name of this syndrome is associated with chromosome number 5, namely a chromosomal abnormality (deletion) in the long arm (q ) chromosome 5. Deletion within the long arm of chromosomeN o 5 is the only chromosomal abnormality in MDS patients diagnosed with syndrome 5q - ".

Typically, this syndrome occurs in middle-aged women, usually around the age of 65, and is accompanied by mild to moderate anemia, low white blood cell count (leukopenia), and often normal or high platelet counts. Syndrome 5q - characterized by a favorable prognosis, life expectancy of more than five years from the time of diagnosis (a criterion adopted in medicine to assess the severity of the disease).

Unclassified MDS. This category includes patients with cytopenia in one type of blood cell (for example, thrombopenia or neutropenia) and any unusual characteristics (for example, bone marrow fibrosis), no more than 1% - 2% of all cases of MDS.

Another system used to characterize MDS activity and make a prognosis for a patient is International predictive score system ( IPSS).

To assess the severity of MDS, the International Predictive Scoring System (IPSS ), the disease is evaluated in points based on the danger it poses to the patient, that is, the time of the probable progression of the disease or its transformation into AML. The predictive score is determined based on the percentage of blasts present in the bone marrow, cytogenetic test results, and blood cell counts and other blood test results.

The predictive score is determined by adding the individual scores for the percentage of blasts, based on the results of cytogenetic studies and blood tests, and is used to assess the outcome of the disease for a patient with MDS. The predictive score shows which of the risk groups the patient belongs to.

Determination of the predictive score Predictive score: the sum of individual scores for blasts, cytogenetic test results and blood test results
Percentage of blasts in the bone marrow	Score
5% or less
5-10%
11-20%
21-30% *	2 , 0
Cytogenetic results research **
good
intermediate
bad
Cytopenia level based on blood test results ***
0 or 1 cytopenias
2 or 3 cytopenias
* Patients whose bone marrow contains more than 20% of blasts are diagnosed with acute myeloid leukemia (AML). ** Predictively good results indicate a normal set of 23 pairs of chromosomes or a set with only partial loss of the long arm of the chromosomeN o 5. Intermediate results include all results that do not fall under the definition of "good" or "bad". Poor predictive outcomes include loss of one of two chromosomesN o 7 (monosomy 7), addition of the third chromosomeN about 8 (trisomy 8), or three or more anomalies. *** The level of cytopenia according to the results of a blood test is determined as follows: neutrophils< 1,800 на 1 микролитр крови; гематокрит < 36% эритроцитов в общем объеме крови в организме; тромбоциты < 100,000 на 1 микролитр крови.

MDS treatment

The goals of treatment are to restore peripheral blood parameters, reduce the clinical manifestations of MDS, reduce dependence on transfusions of blood components, delay transformation into AML, increase life expectancy, and improve the quality of life of patients.

Treatments for patients with MDS depend on the type of disease, prognostic factors, patient age, and comorbidity and can be classified into potentially curative and supportive therapies.

Supportive and symptomatic therapy

The mainstay of MDS treatment is supportive therapy, which includes the use of growth factors, treatment of intercurrent infections, and replacement therapy with blood components.

One of the aspects of maintenance therapy for patients with MDS is the use of hematopoietic growth factors, which act on the bone marrow, enhancing the production of one or more hematopoietic germs. In recent years, several human recombinant growth factors have emerged, including erythropoietins (EPO: epoetins α and β, darbepoetin), garnulocyte and granulocyte-macrophage colony-stimulating factors (G-CSF and GM-CSF: filgrastim, thromgrastim receptors, eltrombopag), which stimulate the production of red blood cells, granulocytes and platelets, respectively. Growth factor treatment, which reduces the need for substitution therapy, is responded to by only 20–30% of patients with MDS. Predictive factors of response to therapy are the initial level of EPO, the severity of the transfusion need, the duration of the disease, the type of disease according to the classificationFAB or WHO, rice group on a scaleIPSS.

Despite the fact that the cost of therapy with hematopoietic growth factors is 3-4 times higher than the cost of transfusion therapy, the former remains the preferred type of treatment. Successful treatment with hematopoietic growth factors avoids or, in some cases, reduces the need for multiple transfusions of blood components and the associated risk of iron overload.

Supportive therapy for patients with MDS is based on blood component replacement therapy. In patients with low risk AML development, anemia may be a major clinically significant problem. Substitution therapy relieves the symptoms of anemia and is therefore an important treatment. The frequency of transfusions depends on the patient's condition, the severity of the anemia, and comorbidities. Some people may need red blood cell transfusions every one to two weeks, while others may need just one transfusion every six to twelve weeks. The result of substitution therapy is an increase in hemoglobin levels, which, according to studies, has a positive correlation with an indicator of quality of life. Platelet transfusion is rarely done and only when platelet count is extremely low and / or life-threatening bleeding is present. However, the benefits of transfusion therapy must be weighed against the risk of infectious complications, immunological side effects, and iron overload in the patient.

The accumulation of excess iron in the body is a serious clinical problem that, if not addressed, can lead to organ damage. Repeated transfusions of erythrocytes containing iron in hemoglobin lead to the deposition of excess iron in the cells of the reticuloendothelial system, primarily in the liver, spleen, endocrine glands and heart, as well as in small amounts in brain tissues or skeletal muscles. Therefore, the main complications of iron overload are heart disease, liver disease and endocrine disorders. In order to prevent an overload of the body with iron, laboratory control over its reserves (serum ferritin) is used, as well as drugs that chelate or bind iron, contribute to its removal from the body.

There are currently two drugs available to combat iron overload in transfusion-dependent patients - deferoxamine and deferasirox.

The drug deferoxamine (Desferal) delays the toxic effect of the accumulation of excess iron in the body. It is given in addition to blood transfusion and is given by injection, usually 3-7 times a week. Some patients receive subcutaneous injections of the drug 2 times a day. Deferasirox (Exjade), a chelator, is taken orally. Treatment with these drugs should be started in patients who have received 20-30 units of donor erythrocytes, who are subject to continuous transfusion therapy, as well as in patients with serum ferritin levels constantly exceeding 1000 μg / L.

Potentially Healing Therapies

Intensive chemotherapy is used to control the symptoms or cure MDS in young high-risk MDS patients to maximize the destruction of the abnormal cell clone and achieve long-term remission.

Patients \u003c55 years of age with high or intermediate 2 risk MDS on the scaleIPSS for those who do not have the ability to transplant stem cells, chemotherapy similar to that used to treat AML may be suitable. This treatment has significant side effects such as hair loss, mouth stomatitis, nausea, vomiting, loose stools... In addition to these side effects, chemotherapy has an adverse effect on healthy cells, along with cells that have undergone dysplastic influences, which requires a long stay in the hematology department. At this time, the patient undergoes transfusions of erythrocyte and platelet mass, and antibacterial drugs are prescribed to fight the infection. If induction chemotherapy provides adequate control of abnormal cells (a state of remission), then the restoration of normal blood cells should begin within a few weeks. Unfortunately, the likelihood of controlling MDS with induction chemotherapy is about 30%. Even in cases of successful treatment, the disease can come back - relapse.

1. The only known treatment that can cure MDS is transplantation of allogeneic (donor) hematopoietic stem cells. It should be borne in mind that this is a complex procedure with the risk of early and late complications. The outcome of treatment depends on the degree of compatibility (HLA -compatibility) of the donor and the patient (recipient), as well as the availability of suitable donor cells (the presence of compatible blood brothers and / or sisters, the availability of the donor bank). Thus, there are strict indications and contraindications for this type of treatment: it is suitable for those cases when patients are able to undergo stem cell transplantation and have a suitable donor. Recently proposed transplant techniques with reduced intensity conditioning regimens have had some success in MDS patients over 55 years of age. Research in this area is ongoing.

2. The involvement of immune mechanisms in the development of bone marrow pathology in MDS has led to the development of methods of treatment with the use of immunosuppressants. Of this group of drugs, anti-thymocyte globulin (ATG) and anti-lymphocyte globulin (ALG) and cyclosporin A are used in the treatment of MDS. Treatment of ALG / ATG is more effective in young patients with the presence of antigenHLA - DR 15 who received transfusion of erythrocytes for a short time. This treatment makes it possible to achieve independence from red blood cell transfusions in 33% of patients; in 56% of patients with severe thrombocytopenia, a significant increase in platelet count was observed, and in 44% of patients with neutropenia, the level of neutrophils increased by more than 1x10 9 / L. Cyclosporin A was found to be most effective in patients with less than 5% blast cells in the bone marrow, normal karyotype, hypocellular bone marrow, and lymphoid cell accumulations in the trepanobiopsy specimen.

3. The study of the mechanisms of development of MDS, undertaken in recent years, has shown that this pathology is characterized by hypermethylation of the promoter region of some oncosuppressor genes, which leads to the "silence" of these genes and the proliferation of tumor cells and transformation into AML. Based on this knowledge, so-called hypomethylating agents have been developed that promote DNA hypomethylation by inducing the expression of previously “turned off” genes.

In May 2004, the United States Food and Drug Administration (Food and Drug Administranion, FDA ) issued a permit to use the injectable drug azacytidine (Vaidaza) for the treatment of all types of MDS. In the Russian Federation, the drug was approved for use in 2010 for the treatment of MDS, AML, and CML. The results of the study showed that azacitidine significantly prolongs the life of patients with intermediate and high-risk myelodysplastic syndrome (MDS), as well as with acute myeloid leukemia 20-30% of blasts (previously referred to high-risk MDS) who are not eligible for stem cell transplantation / intensive chemotherapy ...

According to the protocols adopted in Russia, patients with intermediate-2 / high-risk MDS and AML who are not suitable for intensive chemotherapy are treated with low doses of cytarabine and / or with the help of supportive therapy. Such treatment can alleviate the symptoms of the disease, improve the quality of life of patients, but has no other significant advantages over the natural course of the disease. At the same time, the life expectancy of patients with high-risk MDS receiving azacitidine is increased by 3 times compared with the accepted treatment. At the same time, the differences between the azacitidine group and the groups of maintenance therapy and low doses of cytarabine are statistically significant (p \u003d 0.045), regardless of age or karyotype (analysis of study dataIII phase AZA -001)

Azacitidine increases the number of MDS patients who do not need blood transfusions by 4 times. In addition, azacitidine is indicated as a temporary therapy in patients awaiting a donor for transplantation (recommendations for MDS therapy,NCCN, 2010).

Grade 3-4 adverse events that develop during treatment with azacytidine include hematological (71.4%), including thrombocytopenia (85%), neutropenia (91%) and anemia (57%). Febrile neutropenia occurred in 8.0% of patients, it is extremely rare (<2%) регистрировались нейтропенический сепсис, пневмония, тромбоцитопения и геморрагические нежелательные явления.

Azacitidine is injected subcutaneously 75 mg / m 2 1 r / day 7 days after 21 days (cycle), at least 6 cycles. It has a favorable safety profile and can be used on an outpatient basis.

In May 2006, the committeeFDA approved the use of another hypomethylating drug, decitabine (Dacogen), for the treatment of all MDS subtypes. The drug was approved for use in the treatment of MDS in the Russian Federation in 2006.

In an open randomized trialIII phase with 170 patients comparing decitabine with maintenance therapy, the remission rate was 17%, and hematologic improvement was noted in another 13% of patients. Decitabine reduces the risk of transformation to leukemia and, in patients who achieve a response, increases survival. The likelihood of transformation to acute myeloid leukemia or death was 1.68 times higher in the maintenance group compared with the decitabine group.

During decitabine therapy, the most common side effects were: neutropenia-90%, thrombocytopenia-89%, anemia-82%, fever -53%, nausea-42%.

Decitabine is given intravenously (15 mg / m2 by 3-hour intravenous infusion every 8 hours for 3 consecutive days every 6 weeks for 10 cycles).

Both azacitidine and decitabine therapy should be supervised by a hematologist experienced in treating patients with MDS and AML.

4. In December 2005FDA The USA approved the use of the immunomodulatory drug lenalidomide for the treatment of patients at low or intermediate -1 risk with MDS, including those withdel (5 q ). The drug is administered orally in capsules, has an immunomodulatory, antiangiogenic and antitumor effect. At the same time, it lacks the neurotoxicity inherent in other drugs from this chemical group. The incidence of remission during treatment with lenalidomide was 83% in patients with clonal interstitial deletion of chromosome 5q 31.1, while in patients with normal karyotype, the remission rate was 57%, and in patients with other karyotype abnormalities - 12%. In researchII phases involving 146 patients with low or intermediate 1 risk MDS withdel (5 q 31) requiring continuous transfusion therapy, 64% of patients stopped needing transfusions. The incidence of transfusion independence was higher among patients with isolateddel (5 q ) (69%) than in other patients (49%; P \u003d 0.003).

In February 2012, a lenalidomide file was accepted by the European Medical Agency for registration of this indication - “for the treatment of patients with low / intermediate-1 risk MDS, a variant of transfusion-dependent anemia withdel (5 q ) with / without other cytogenetic abnormalities ”.

Thus, myelodysplastic syndromes (MDS) are a heterogeneous group of bone marrow diseases characterized by ineffective hematopoiesis and varying degrees of risk of transformation into acute leukemia. Diagnosing MDS can be difficult because it shares similarities with other hematologic disorders, including AML, aplastic anemia, and hereditary sideroblastic anemia. Research into the disease mechanisms that lead to MDS is helping us to better understand MDS. Equally important, a better understanding of the mechanisms of the disease is leading to the development of new drugs for the treatment of different subtypes of MDS in patients belonging to different risk groups.

It is only recently that MDS treatment has expanded beyond supportive care given to relieve symptoms. The only potentially curative treatment for MDS is allogeneic hematopoietic cell transplantation, which, however, is not possible in all cases.

In recent years, based on the study of the pathogenesis of this pathology, a large number of drugs have been developed, some of which will find their place in the treatment of MDS. Examples include the angiogenesis inhibitor bevacizumab (Avastin), the cytokine inhibitor infliximab (Remicade), deacetylase inhibitors, histone inhibitors valproic acid and vorinostat, and many others. Scientific evidence suggests that combination therapy with drugs with different mechanisms of action will lead to the desired treatment efficacy.

But whichever therapeutic strategy is ultimately chosen, it must take into account the patient's decision.

Materials are presented from the RUDN University textbook

Anemia. Clinic, diagnosis and treatment / Stuklov N.I., Alpidovsky V.K., Ogurtsov P.P. - M .: LLC "Medical Information Agency", 2013. - 264 p.

Copying and duplicating materials without specifying the authors is prohibited and punishable by law.

Myelodysplastic syndrome (MDS) unites a group of acquired diseases of the hematopoietic system, in which the pathological process begins at the level of a pluripotent stem cell and reveals itself as a violation of the proliferation and differentiation of cells of one, two or three hematopoietic germs with their subsequent death in the bone marrow (ineffective erythropoiesis).

Unlike AA, stem cells are present in the bone marrow of MDS patients, although they are functionally deficient. Bone marrow in MDS is more often hypercellular, normocellular, and less often hypocellular, while refractory anemia, often leuko- and / or thrombocytopenia, is found in the peripheral blood.

The functional pathology of pluripotent stem cells is based on chromosomal changes that are found in most patients with MDS. They have a clonal character, similar to cytogenetic changes in leukemia. Chromosomal changes in MDS are diverse and include translocation, inversion, and deletion of chromosomes. The most typical are: trisomy 8, monosomy 5, monosomy 7, deletion of the Y chromosome, deletion of the long arm 7 (7q-), 11 (11q-), 13 (13q-), 20 (20q-), as well as t (1; 3), t (5; 7), t (2; 11), t (6; 9), t (11; 27), inversion of chromosome 3. Multiple disorders are observed in 20% of patients. Deletion of the long arm of chromosome 5 is common (in 30% of patients). Moreover, it was found that with this arm of chromosome 5, genes are lost that are responsible for the synthesis of many germ factors, including granulocyte-macrophage, IL-3, IL-4, IL-5, IL-6 and many other biologically active substances that regulate hematopoiesis ...

A form with a similar chromosomal abnormality was even identified among MDS patients in 5q - the syndrome, which is more common in women, is characterized by refractory megaloblastic anemia and rarely transforms into acute leukemia (less than 5% of patients).

The causes of chromosomal abnormalities are unclear. In some cases, the action of mutagenic factors such as ionizing radiation, the action of chemical and medicinal factors is assumed.

The cytogenetic pathology that has arisen in the bone marrow in one pluripotent stem cell, which determines the further development of MDS, is able to reproduce in the descendants of the confused stem cell, thus forming a pathological clone, whose cells are not capable of normal proliferation and differentiation, which is externally manifested by their morphological dysplasia and subsequent bone marrow death (ineffective erythropoiesis). It was found that 75% of the bone marrow in MDS haveCD 95, a marker of programmed cell death - apoptosis. This causes different types of cytopenias in the peripheral blood of MDS patients.

The incidence of MDS is 3-15 cases per 100,000 population and its frequency rises to 30 cases in people over 70 years old and 70 cases over the age of 80 years. The average age of patients is 60 - 65 years, MDS is extremely rare in children.

Clinic

The clinical picture of MDS has no specific features. The main symptoms depend on the depth and combination of damage to the hematopoietic germs. The main symptom of the disease is refractory anemic syndrome, manifested by increasing weakness, increased fatigue and other symptoms characteristic of anemia. In patients with MDS with leukopenia, infectious complications often occur (bronchitis, pneumonia, etc.). Hemorrhagic syndrome due to thrombocytopenia is observed in 10 - 30% of patients, and is manifested by hemorrhages on the skin and visible mucous membranes, bleeding gums and nosebleeds.

There is no characteristic organ pathology in MDS: peripheral lymph nodes, liver and spleen are not enlarged.

Laboratory data.

Anemia varying degrees of severity is observed in almost all patients with MDS and often wears macrocytic character. Hypochromia of erythrocytes is very rarely observed. Elliptocytes, stomatocytes and acanthocytes are often present, as well as basophilic puncture and Jolly's bodies in erythrocytes. In the blood, nucleated cells of the red row may be present. The number of reticulocytes is often reduced.

Patients often have persistent blood tests. neutropenia, and granulocytes are characterized by the presence pseudopelgerian anomaly (leukocytes with bipartite nuclei and cytoplasmic degranulation).

Thrombocytopenia occurs in half of patients with MDS. Giant and degranulated forms are found among platelets.

In some patients with MDS, blood tests may include blast cells.

Bone marrow in MDS, it is usually hypercellular, but it can be normocellular, and in rare cases, even hypocellular. However, there are always features dyserythropoiesis: megaloblastoid, multinucleated erythroblasts, the presence of mitoses, pathological divisions and nuclear anomalies, bridges between them, basophilic puncture and vacuolization of the cytoplasm. In some patients, the bone marrow has an increased content of sideroblasts with an annular arrangement of iron granules around the cell nucleus.

Impaired differentiation of erythrocyte precursors in MDS is manifested by an increased content in themHbF (the level of which in mature erythrocytes is normal) and the presence of peroxidase and alkaline phosphatase in erythroblasts, which is characteristic of neutrophils.

Dysgranulocytopoiesis in the bone marrow it is manifested by a delay in the maturation of granulocytes at the level of myelocytes, a violation of the process of granulation of the cytoplasm and a decrease in the activity of alkaline phosphatase, which indicates their functional inferiority, hypo - or hypersegmentation of neutrophil nuclei is often found.

Dysmegakaryocytopoiesis characterized by the predominance of microforms and impaired lacing of platelets.

In some forms of MDS, an increased content of blast cells in the bone marrow is detected (from 5 to 20%).

In a histological examination of the bone marrow obtained by trepanobiopsy, a number of patients have an increased formation of reticulin fibers, and pronounced myelofibrosis is observed in 10-15% of patients with MDS. This variant of MDS, characterized by more pronounced hyperplasia and dysplasia of the cells of the megakaryocytic lineage, with almost 100% presence of chromosomal abnormalities, is characterized by more pronounced anemia, thrombocytopenia and a relatively short life expectancy of patients (median survival 9-10 months).

Diagnosis of MDS based on the presence of refractory anemia resistant to vitamin therapyB 12 , folic acid, iron and other hematics, which is often combined with neutro- and thrombocytopenia and the presence in the bone marrow punctate of morphological signs of dysgematopoiesis (disorders of maturation of hematopoietic cells).

MDS classification:

Currently, two classifications are used in clinical practice: the Franco-American-British group (FAB ) 1982 and the World Health Organization (WHO) 2008.

Differential diagnosis

RA most often has to be differentiated from vitaminB 12 - and folate deficiency anemia, in which there is also megaloblastic hematopoiesis and morphological signs of dysplasia of red cell cells, indicating ineffective erythropoiesis. Rapid clinical and hematological responses to vitamin therapyB 12 or folic acid indicate a causal relationship between anemia and a deficiency in these vitamins.

RACS must be differentiated from acquired sideroblastic anemia due to chronic lead intoxication. RCMD, in which there is pancytopenia in the peripheral blood, resembles aplastic anemia. The presence of normal bone marrow cellularity with morphological signs of dysmyelopoiesis allows correct verification of the diagnosis.

IBS classification (WHO, 2008)

Nosological form of MDS	Changes in blood	Bone marrow changes
Refractory anemia (RA)	Anemia Blasts< 1% Monocytes< 1 х 10 9 / л	- dysplasia of hematopoiesis < 10% в одном ростке кроветворения Blasts< 5% - annular sideroblasts < 15%
Refractory neutropenia (RN)	Neutropenia Blasts< 1% Monocytes< 1 х 10 9 / л
Refractory thrombocytopenia (RT)	- thrombocytopenia Blasts< 1% Monocytes< 1 х 10 9 / л
Refractory anemia with annular sideroblasts (RAKS)	Anemia Blasts< 1% Monocytes< 1 х 10 9 / л	- dysplasia of hematopoiesis. Blasts< 5% - annular sideroblasts > 15%
Refractory cytopenia with multi-germ dysplasia (RCMD)	- cytopenia in 2 - 3 sprouts Blasts< 1% - monocytes< 1 х 10 9 /л	- dysplasia of hematopoiesis < 10% в двух и более ростках кроветворения Blasts< 5% - annular sideroblasts (any number)
Refractory anemia with an excess of blasts I (RAIB-1)	Any cytopenia Blasts< 5% - monocytes< 1 х 10 9 /л	Blasts 5 - 9%
Refractory anemia with an excess of blasts II (RAIB-2)	Any cytopenia Blasts 5 - 19% - monocytes< 1 х 10 9 /л	- multiple dysplasia in all hematopoietic germs Blasts 10 - 19% Auer's sticks ±
MDS unclassified (MDS-N)	Any cytopenia Blasts<1%	- dysplasia of hematopoiesis < 10% в одном или несколь- which sprouts of hematopoiesis Blasts< 5%
5q- syndrome	Anemia Blasts< 1% - platelets are normal or increased	- normal or increased numbers of megakaryocytes with hyposegmented nuclei - isolated 5q deletion Blasts< 5%

It is much more difficult to distinguish the hypoplastic variant of MDS from AA. Hypoplasia in MDS is supported by the presence of a chromosomal pathology that is absent in AA, a high content of pro-apoptotic proteins on hematopoietic cells (CD 95) and a low level of alkaline phosphatase in granulocytes in MDS, in contrast to the normal content of this enzyme in AA, MDS with an excess of blasts differs from acute leukemia in the quantitative content of blast cells in the bone marrow: all cases with blastosis of more than 20% are considered acute leukemia.

Treatment

Symptomatic therapy

The leading place in the treatment of MDS is taken by supportive therapy, first of all - transfusion of erythrocyte mass, accompanied by the introduction of desferal or deferasirox to remove excess iron. Red blood cell transfusion is indicated when the level ofHb up to 80 g / l and below, and its frequency depends on the dynamics of indicators of red blood. To combat hemorrhagic diathesis, the introduction of thrombocyte concentrate is used, the indications are the same as in the treatment of AA. With infectious complications caused by granulocytopenia, antibiotics are indicated.

Pathogenetic therapy depends on the number of blasts to the bone marrow. With severe blastosis (\u003e 10%), sternal punctures should be performed regularly to exclude the transformation of MDS into acute leukemia (acuteleukemia, AL ). With an increase in blasts of more than 20%, therapy is carried out according to treatment programsAL.

Algorithm for the treatment of MDS (Savchenko V.G., Kokhno A.V., Parovichnikova E.N.)

Bone marrow cellularity
Hypocellular bone marrow		Normo/ hypercellular bone marrow
< 5% бластов	5 - 20% blasts	< 5% бластов	5 - 20% blasts
SuA	SuA	rhEPO	Decitabine, Azacitidine
ATG	ATG	Splenectomy	FLAG, 7 + 3
Splenectomy	Decitabine, Azacitidine	Interferon-α	MDC - 14 days
rhEPO	MDC - 14 days, 6 - MP, melphalan	Decitabine, Azacitidine	6 - MP

In cases where the number of blasts in the bone marrow is persistently below 20%, a trepanobiopsy is necessary to make a decision on treatment tactics, which allows to establish the cellularity of the bone marrow. After that, MDS therapy can be aimed at stimulating hematopoiesis in case of bone marrow hypoplasia (recombinant human erythropoietin - rh-EPO), immunosuppression in order to activate stem cells (ATG,CyA ), decreased hemolysis and sequestration of blood cells (splenectomy). In hypercellular variants or forms of MDS with blastosis of more than 5%, treatment should include suppression of tumor growth (chemotherapy). In Russia, the most appropriate algorithm for choosing MDS therapy, the scheme of which is shown in the table, was formulated by specialists of the Hematological Research Center: Savchenko V.G., Kokhno A.V., Parovichnikova E.N. in 2012.

In recent years, rhEPO has been used, sometimes successfully, to stimulate erythropoiesis in MDS patients: Recormon, Erythrostim, Eprex, Aranesp, etc., which is especially effective at a low concentration of native EPO in the blood (< 500 ед/мл). РчЭПО рекомендуется применять в дозе 100000 МЕ 3 раза в неделю подкожно или по 30000 – 40000 МЕ раз в неделю (при использовании пролонгированных форм эритропоэтина). Терапия считается эффективной при приросте гемоглобина более чем на 10 г/л за 4 – 8 недель или снижение зависимости от гемотрансфузий. Целевая концентрация гемоглобина 120 г/л. Через 2 месяца лечения рчЭПО сообщается о положительном эффекте у 41,6% больных с РА и у 76% больных с РАКС, причем к 6 месяцу этот эффект сохраняется соответственно у 33% и 58%. Таким образом, наиболее effective application EPO was found in patients with the MDS-RAKS variant.

In more than a third of MDS patients, the severity of thrombocytopenia can be temporarily reduced by the administration of interferon-α, this avoids alloimmunization caused by the administration of thromboconcentrate. Therapy with glucocorticoids in MDS is not effective, although it can sometimes reduce the intensity of hemorrhagic syndrome.

In MDS patients with a hypoplastic phase of the disease, as in AA, immunosuppressive therapy (CyA) proved to be effective, which not only blocks the action of suppressor T cells, but also inhibits cell apoptosis. Cyclosporin A is prescribed at a dose of 5 mg / kg and causes hematological improvement in 60 patients in this group (complete remissions develop less often, partial improvement more often).

For the treatment of forms of MDS RA, RAKS, RCMD, splenectomy with liver biopsy is currently widely used as a primary method of treatment in elderly (over 60 years old) patients with hematopoietic hypoplasia or resistance to cyclosporine. Along with the therapeutic effect, this approach allows you to exclude other causes of the development of hematopoietic dysplasia. As a rule, splenectomy allows you to achieve long breaks in blood transfusions, improve the quality of life of patients.

The use of cytostatic drugs in the RAEB-variant of MDS is currently considered the most effective treatment. Until recently, mainly small doses of Cytosar and melphalan were used as pathogenetic therapy. The treatment regimen with low doses of Cytosar is as follows. Injected subcutaneously at 10 mg / m 2 2 times a day for 14, 21 or 28 days, depending on the number of blasts and bone marrow cellularity. Melphalan is used in doses of 5-10 mg / m 2 for 5 daysperos ... Such courses are carried out once a month, as a rule, from half a year to 3 years, with an assessment of the therapeutic effect every 2 to 4 months. An effective therapy is considered when the parameters of peripheral blood and bone marrow are normalized or relatively normalized, in the absence or a sharp decrease in dependence on blood transfusions. The use of these treatment regimens leads to the development of partial remission in 56% of patients. However, such therapy does not significantly affect the survival of patients.

When grave condition patients and the impossibility of carrying out adequate therapy with MDS-RAEB-1 and -2, it is possible to prescribe 6-mercaptopurine at 60 mg / m2 per dayperos for 3 years.

At present, attempts are being made to use thalidomide and its analogue lenalidomide, which is devoid of neutrotoxic activity, but is a potent protease inhibitor, in the treatment of MDS. The use of lenalidomide caused a decrease in transfusion dependence in 67% of patients, and in 58%, complete independence from transfusion therapy was achieved. It should be noted that this drug is especially effective at 5q - a variant of MDS, where its effectiveness is 91%, while with other violations of the karyotype - only 19%.

In young patients under 60, polychemotherapy is included in the MDS-RAIB-2 treatment standards. The courses used in the treatment of acute myeloblastic leukemias are used: "7 + 3" and "FLAG ". "7 + 3": cytarabine 100 mg / m 2 IV drip every 12 hours 1 - 7 days of the course and idarubicin 12 mg / m 2 IV drip 1 - 3 days of the course. "FLAG ": Fludarabine 25 mg / m 2 intravenous drip 1 - 5 days of the course, cytarabine 2 g / m 2 intravenous drip 1 - 5 days of the course + G-CSF (granulocyte colony-stimulating factor) 5 μg / kg s / c daily before exiting cytopenia.

Among other actively developed drugs in hematological practice, arsenic trioxide, bevacizumab (Avastin), etc. deserve attention.

Recently, modern cytostatic drugs, inhibitors of DNA methyltransferases, have been introduced into clinical practice. The mechanism of their action is associated with inhibition of the process of DNA methylation in the cells of the tumor clone, which leads to an increase in the activity of genes that regulate the cell cycle and the normalization of differentiation of bone marrow cells. Two main substances are registered in Russia under the name decitabine (Dacogen), azacytidine (Vedaza). According to the published data of the largest international studies, the effectiveness of using these drugs in the treatment of MDS was 50 - 70%. Decitabine is administered at a dose of 20 mg / m 2 intravenous drip 1 - 5 days once a month. Such courses are carried out4, then the effect is assessed. With a positive assessment, therapy is continued for a long time until complications develop, in the absence of an effect, other drugs are used. Azacitidine is injected subcutaneously with 75 mg / m 2 for 1 to 7 days, once a month. The effect is assessed after six months, then either the therapy is continued for a long time or the drugs are changed.

You need to know that the most serious complication of chemotherapy, sometimes requiring discontinuation of treatment, is cytopenia. Cytopenia, as a rule, is manifested by a decrease in all blood parameters (Hb , leukocytes and platelets). Severe life-threatening conditions are considered anemia less than 70 g / l, thrombocytopenia less than 20 x 10 9 / l, leukopenia less than 1 x 10 9 / l or neutropenia less than 0.5 x 10 9 / l. Such conditions require compulsory inpatient treatment, transfusion and antibiotic therapy.

The only radical treatment for MDS could be allogeneic bone marrow transplantation, however, the use of this method is limited to elderly patients, the vast majority of whom are over 60 years old.

Forecast with MDS, it remains unfavorable and depends on the variant of MDS. In RA, transformation into acute leukemia is observed in 15% of patients, and the median survival is 50 months. In case of RAKS, these indicators are 8% and 51 months, respectively; with RAIB - 44% and 11 months.

One of the serious diseases of the hematopoietic system is myelodysplastic syndrome. The disease is difficult to treat, which is not always effective. Further prognosis after the establishment of the pathology depends on many features of the course of the disease. Often, only radical therapy, carried out in the early stages of the development of pathology, can save the patient's life.

General understanding of the disease

MDS syndrome is used by specialists to designate the spectrum of various pathologies characterized by cytopenia in the blood and the spread of pathological changes affecting the bone marrow.

Each disease poses a danger to humans and can provoke the development of an acute form of myeloblastic syndrome.

Experts pay sufficient attention to the disease, which is due to an increase in the number of cases. However, there is no specific treatment regimen.

In addition, myelodysplastic syndrome is more likely to be detected in young people. According to experts, this is due to the poor environmental situation.

The risk group includes mainly people over the age of 50. Pathology in children manifests itself in the most extreme cases.

In modern medicine, myelodysplastic syndrome can be divided into primary and secondary forms. The first type is often detected in patients over 60 years old. The secondary syndrome is established regardless of the age group and is a complication of another disease.

Classification

Myelodysplastic syndrome is a group of certain diseases that have a similar mechanism of development and other characteristics. According to WHO, there are several classifications.

Refractory anemia

The disease manifests itself in the form of an insufficient number of red blood cells in the blood. But with refractory anemia, the level of platelets and leukocytes does not change and remains unchanged.

The main diagnostic method is plasma research. If necessary, other methods of examination can be prescribed.

Refractory anemia with annular sideroblasts

Based on the results of a blood test, an insufficient number of red blood cells is established. The cells have a high iron content.

But despite the violations, the platelet level does not change and remains at the same level.

Refractory anemia with a lack of blasts

With the disease, there is an insufficient number of blasts in the blood, which are at the stage of transformation.

In addition, a lack of red blood cells is found in the plasma. The level of platelets and leukocytes is also not within the normal range. The violations are insignificant.

The bone marrow contains no more than 19%, but no less than 5% of blasts.

Refractory cytopenia

Most often combined with multilinear dysplasia. A decrease in two or more indicators is observed in the blood.

No more than 5% of the blasts contained in the bone marrow are observed. In the blood moving along the periphery, their content does not exceed 1%.

Over time, in the absence of therapy or improper treatment, pathology can transform into leukemia.

MDS syndrome with chromosome abnormalities

The lack of red blood cells is determined in the blood. The number of blasts in the bone marrow, as in the case of refractory cytopenia, does not exceed five percent. In plasma, no more than 1% is found.

Chromosomes undergo certain changes, the cause of which is the pathological process.

In the medical literature, unclassified myelodysplastic syndrome is distinguished. It is characterized by a significant decrease in blood cell counts. At the same time, the level of blasts in both plasma and bone marrow remains in a normal amount and does not undergo changes.

Clinical picture

Myelodysplastic syndrome manifests itself in the form of weakness and shortness of breath at the initial stages of its development. But in some cases, the disease may be asymptomatic.

Most often, the pathology is established randomly, when the patient donates blood for analysis in the presence of another disease or for the purpose of a preventive examination.

Over time, symptoms develop that are often confused with liver disease or autoimmune disorders.

The patient complains of the following symptoms:

1. Pallor skin.
2. Frequent colds and ARVI.
3. The appearance of punctate subcutaneous hemorrhages.

After minor injuries and bruises, a bruise or bruising occurs at the impact site. Over time, when the disease progresses, and the patient does not receive treatment, other signs are added to the main symptoms.

Among the clinical manifestations, subcutaneous bruising is observed, which affects a significant part of the skin, pain in joints and bones, and weight loss.

According to the results clinical research blood, there is a sharp and significant decrease in hemoglobin. Patients have difficulty breathing with no signs of asthma at all.

After minor physical exertion, weakness appears, the body quickly gets tired. Weight loss occurs against the background of loss of appetite. In some cases, the body temperature may rise up to 40 degrees.

All symptoms have varying degrees of severity, depending on the period of development of the disease and the characteristics of the patient's body.

Why does myelodysplastic syndrome occur?

Scientists could not find out the true reasons for the development of pathology even after the research. But a number of factors have been established that can affect the composition of the blood and provoke the development of the syndrome.

It has been proven that the primary type of pathology affects most often people over the age of 60. Its occurrence can be influenced by such factors as genetic predisposition, unfavorable environmental conditions, high level radiation, work in harmful working conditions.

Also, MDS can occur with constant work with toxic, chemical and poisonous substances, due to smoking and drinking alcohol. Experts have found that hereditary diseases such as Down's syndrome, neurofibromatosis and Fanconi's anemia have a significant impact on the development of pathology.

Secondary myelodysplastic syndrome, according to the results of the studies carried out, occurs against the background of chemotherapy, taking a number of potent medicines or radiation therapy.

Secondary MDS occurs regardless of age group. When it is detected, the prognosis is most often unfavorable, since the disease has a rapid course and has a negative effect on all organs and systems.

Diagnostic methods

Myelodysplastic syndrome is established based on the results of laboratory blood tests and bone marrow histology. The doctor also examines the anamnesis, which helps to determine the patient's lifestyle, the presence of occupational hazards, and genetic predisposition.

A number of instrumental methods and laboratory tests are also prescribed to establish a complete picture of the disease.

Hemogram

A laboratory blood test that detects the presence of anemia, neutropenia, or monocytosis. When pencytopenia is established, the patient is assigned a histological examination of bone marrow samples.

Biochemical analysis

Helps determine the level of iron in the blood, as well as folic acid, urea and alkaline phosphatase.

Blood must be donated in morning time on an empty stomach. Exercise, eating, stress and smoking are prohibited before the procedure.

Immunogram

This is a comprehensive blood test that helps a specialist determine the state of immunity.

Decreased indicators indicate that the defenses are suppressed, and the body is not able to cope with the disease on its own.

Histology

Before the laboratory test, a biopsy is done, in which the specialist takes a sample of the bone marrow. For this, a special device is used, at one end of which there is a special needle.

The resulting samples are sent to the laboratory, where they are examined under a microscope. According to the results of the study, the presence or absence of cancer cells is established.

Cytochemical research

This diagnostic method allows you to identify a violation of the metabolism of vitamins and various microelements in the body.

Ultrasound, CT and MRI

Ultrasound, computed tomography, or magnetic resonance imaging can help identify impaired performance internal organs.

Based on the studies obtained, the specialist determines the degree of development of the disease, the degree of changes in the work of internal organs, decreased immunity and other features of the course of the disease.

Also, the doctor must necessarily conduct differential diagnosis, since myelodysplastic syndrome in its clinical manifestations is similar to the following diseases:

1. Leukemia acute form.
2. Diseases liver.
3. Disruption of exchange protein compounds in the body.
4. Poisoning toxic and poisonous substances, vapors.
5. Lymphoma malignant nature.
6. Myelodepressant syndrome.

Only after a comprehensive study and study of the results, a specialist can establish an accurate diagnosis and conduct therapy.

Treatment of MDS syndrome

It is believed that the only effective way therapy for the establishment of MDS syndrome is bone marrow transplantation. But this method, first of all, does not always bring the desired result and has a number of disadvantages: the cost of the procedure is quite high, there is a high probability of rejection of the transplanted cells and the need for a number of studies to prepare the patient for transplantation.

Often, the operation can be postponed indefinitely due to the absence of a donor.

Before the bone marrow cell transplant procedure, the patient will have to undergo a course of chemotherapy. But the method does not always bring the desired result. In addition, after the course of treatment, side effects occur in the form of damage to cells of internal organs, loss of hair, nails, nausea, and a significant decrease in immunity.

For chemotherapy, modern drugs are used, such as Decitabine or Cytarabine. The dosage of the funds is selected individually, depending on the degree of development of the pathology, the condition and age of the patient, as well as other features of the course of the disease.

Today, experts also believe that stem cell transplantation is an effective way to treat pathology. But after the procedure, unwanted effects may occur. Stem cell transplantation can reduce the risk of acute leukemia, which is life-threatening for the patient.

At the initial stages of the development of the disease, blood transfusion is used, due to which unpleasant symptoms completely disappear. Donated blood is most often injected in the form of erythrocyte mass or thrombocyte concentrate.

In some cases, concomitant therapy is prescribed, which is carried out over a short period of time. This is because too much iron in the blood can cause serious complications.

To stimulate the production of blood cells, drugs such as Leukin, Neupogen or Erythropoietin are prescribed.

When the myelodysplastic syndrome is established, the patient is prescribed funds to increase and maintain the body's defenses. To rule out the occurrence of leukemia, they are usually given intravenously.

Possible complications

Myelodysplastic syndrome is characterized by damage to the bone marrow and changes in the number of blood cells. In the absence of therapy, anemia develops.

Against the background of insufficient blood cells, the development of heart failure is observed, the likelihood of infection with viruses, fungi and infectious microorganisms significantly increases.

MDS syndrome, complicated by anemia, is characterized by fatigue. Frequent dizziness. But it is believed that the disease is mild.

As a result of insufficient blood cells, immunity decreases, the body becomes susceptible to various infectious lesions. This leads to the development of pneumonia, stomatitis, laryngitis and other pathologies.

With an insufficient number of platelets, a violation of blood coagulation occurs. For this reason, even minor damage to soft tissues can be fatal.

Blood cancer and MDS syndrome

MDS syndrome and blood cancer are closely related. An advanced disease often leads to the transformation of healthy cells.

But cancer does not occur in all cases.

Blood cancer is diagnosed only when myelodysplastic syndrome is a secondary condition. The cause of cell mutation is the active substances of the drugs used for chemotherapy. In this case, the disease passes in acute form and hardly amenable to drug treatment.

How many live

The further prognosis in the establishment of the syndrome depends on many factors. The pathogenetic type of pathology is of considerable importance.

A more favorable prognosis is observed when the disease is of the primary type. With the help of radical therapy, it is possible to significantly increase the patient's life.

An unfavorable prognosis is established in cases when the syndrome began to develop while taking chemotherapy drugs and has a secondary form. However, it most often transforms into blood cancer.

On average, when a high degree of risk is identified, life expectancy is no more than six months.

That is why, in the event of symptoms, you should consult a doctor. Signs do not always indicate this disease, but timely diagnosis can significantly reduce the risk of complications.

Prophylaxis

There are no special rules for preventing the development of myelodysplastic syndrome. Experts recommend using general measures.

To reduce the risk of developing blood cancer, patients are advised to comply with the following requirements:

1. Strengthen immunity. To do this, you need to go in for sports and temper. Multivitamins will help support the body's defenses.
2. Correctly eat. The diet should include fruits, vegetables and berries. You need to give up fast food and fast foot.
3. Maintain level hemoglobin at the right level. You can find out the indicators by taking a blood test for hemoglobin. The results can be obtained from the attending physician after 2-7 days.
4. Daily walk in the fresh air. Even a five minute walk will be beneficial. But before going out, you should definitely dress for the weather, so as not to freeze and sweat.
5. The skin must be protected from exposure chemical substances.

Patients should donate blood for analysis in a timely manner and regularly visit a doctor for a preventive examination.

Myelodysplastic syndrome refers to severe damage to the bone marrow, characterized by a change in the composition of the blood. It is important to carry out treatment in a timely manner, since the disease can cause serious consequences.

The 1930s of the XX century are a time of rapid development of medicine and hopes for a universal triumph of progress. But life is a harsh and hard lady. First, the world was faced with a war, and then pundits who, 20 years ago, were burning with dreams, told humanity that cancer is the scourge of our time. The myelodysplastic syndrome, which we will talk about today, is not one of the common ones, but it finds its victims regularly. And what does a patient who has been told of a disappointing diagnosis most often do? That's right, he begins to mourn his fate and is given to despondency. And instead of fighting the problem, he gives up. There is no need to talk about what the ending is like in this case.

Why did we decide to start with such a disappointing introduction? The answer is simple. You must understand that with the current level of development of medicine, oncology is precisely a diagnosis (where the prognosis is far from so obvious), and not a reason to engage in the drawing up of a will. Heavy, requiring maximum stress from the patient and his relatives, and from doctors - an unconditional conviction of a successful outcome of treatment. In other words, modern oncology is not only (and not so much!) The latest techniques, super-effective drugs and expensive equipment, but a spirit of success and faith in a small, but such a desired and expected miracle. Please remember this!

You need to know the enemy by sight: we understand the theory

Myelodysplastic syndrome is not an isolated pathology, as ordinary people mistakenly believe, but a group of diseases that affect the bone marrow, which is responsible for blood production. In a healthy person, the natural loss of cells is compensated, which is why their level is kept at about the same level. In other words, in this case, there is a kind of blood circulation in the body: the spleen "destroys" it, and produces the bone marrow. The syndrome disturbs the established balance, causing the level of platelets, erythrocytes or leukocytes to fall. The forecast (about him - at the end of the article) is conditionally unfavorable.

Therefore, this disease is considered in some sense "inconvenient": in the end, removing a tumor in one organ (liver, lungs or stomach) and "strangling" the remaining cancer cells with chemistry or radiation is one thing, but an effective and safe treatment for the patient - completely different.

It is also important to remember that some types of disease (refractory anemia with an excess of blasts) are related to the problem we are considering, but stand apart and require a different approach to treatment, although their diagnosis is standard for such pathologies. Because of this, the patient has to pound the doctors' offices for weeks before the doctors understand what problem they are dealing with. In the meantime, refractory anemia will destroy the body so much that no treatment other than palliative can be offered.

Another point that negatively affects the prognosis of recovery concerns age. In the overwhelming majority of cases, the syndrome is diagnosed in the elderly, those who, due to their age, have "amassed" a bunch of sores, and the body's own protective resources are almost exhausted.

Classification and existing species

1. RA - refractory anemia

• changes in blood: anemia, no blasts;
• changes in the bone marrow: dysplasia of the erythrocyte lineage, blasts< 5%, кольцевых сидеробластов < 15%.

2. RCMD - refractory cytopenia (with multilinear dysplasia)

• changes in blood: cytopenia (two-growth) / pancytopenia, no blasts and Auer's rods, monocytes< 1х10 9 ;
• < 5%, нет палочек Ауэра, кольцевых сидеробластов < 15%.

3.5q - myelodysplastic syndrome (with isolated 5q deletion)

• changes in blood: anemia, blasts< 5%, тромбоциты в норме;
• bone marrow changes: blasts< 5%, нет палочек Ауэра, изолированная делеция (5q).

4. MDS-N - unclassified myelodysplastic syndrome

• changes in blood: cytopenia, no blasts and Auer's rods;
• changes in the bone marrow: single sprout dysplasia (granulocytic or megakaryocytic), blasts< 5%, нет палочек Ауэра.

5. RAKS - refractory anemia (with annular sideroblasts)

• changes in blood: anemia, no blasts;
• changes in the bone marrow: isolated dysplasia of one germ (erythroitic), blasts< 5%, кольцевых сидеробластов > 15%.

6. RCMD-KS - combination of 2 and 5 types

• changes in blood: cytopenia, no blasts and Auer's rods, monocytes< 1х10 9 ;
• bone marrow changes: extensive dysplasia (more than 10%), blasts< 5%, нет палочек Ауэра, кольцевых сидеробластов > 15%.

7. RAEB-1 - refractory anemia, characterized by redundancy of blasts-1

• changes in blood: cytopenia, blasts< 5%, нет палочек Ауэра, моноцитов < 1х10 9 ;
• bone marrow changes: general dysplasia (one or more germs), blast cells from 5% to 9%.

8. RAEB-2 - refractory anemia, characterized by redundancy of blasts-2

• changes in blood: cytopenia, blasts from 5% to 19%, Auer's sticks, monocytes may be present< 1х10 9 ;
• changes in the bone marrow: general dysplasia (one or more germs), blast cells from 10% to 19%, there are Auer sticks.

Diagnostic Gold Standard

Diagnostics is a very imprecise science. And, although the complex of all the above methods is considered to be exhaustive and sufficient today, due to the age factor (there are practically no children with the syndrome, most patients have already crossed the 60-year mark), its implementation is fraught with considerable difficulties. And the point here is not so much in the high trauma of the procedures, but in natural age-related changes... Therefore, the formulation of the correct diagnosis is a non-trivial and rather difficult task.

Some diseases and pathologies (the list is given below) may have similar symptoms, therefore it should be remembered that the diagnosis should be differential:

• various hemoblastosis (erythremia, AML - acute myeloid leukemia, polycythemia vera);
• malignant lymphomas of various etiologies;
• some autoimmune diseases (the prognosis itself is poor);
• toxic damage to the body;
• myelodepressive syndrome;
• HIV (if treatment with highly active antiretroviral drugs has not been carried out);
• protein metabolism disorders;
• chronic liver disease;
• glycogenosis.

Complaints and clinical manifestations

Possible risk factors

• genetic or chromosomal abnormalities;
• prolonged contact with harmful chemicals without adequate protection;
• exposure to radiation.

The above list is very conditional and it is explained quite simply. The syndrome is one of those diseases, the root causes of which have not yet been fully identified, and the existing theories, with an unbiased approach, do not stand up to criticism and can be refuted.

Principles of modern treatment

If all of the above methods for one reason or another (age, stage of the disease, concomitant pathologies, severe symptoms) turned out to be ineffective, it is possible to use palliative treatment. It is not able to help the patient to recover, but to remove pain syndrome and is capable of improving the quality of life. We especially note - it is life (no matter how short it may be), and not aimless living alone with your problems.

Forecast

If we focus on the prognostic system WPSS, developed by WHO, the effectiveness of treatment depends on three main factors:

• karyotype (bad, medium, good): from 2 to 0 points;
• type of disease: RAIB-2 - 3 points; RAIB-1 - 2 points; RCMD, RCMD-KS - 1 point; RA, 5q, RAKS - 0 points;
• need for blood transfusions: yes - 1 point, no - 0 points.

All points are summed up and, on their basis, an indicator of the risk group is displayed, which gives an approximate idea of \u200b\u200bthe possible life span:

• 0 points: 136 months;
• 1 point: 63 months;
• 2 points: 44 months;
• 3-4 points: 19 months;
• 5-6 points: 8 months.

But there are two things to keep in mind here. First, medicine does not stand still, so it is possible that in a few years the situation will change significantly for the better. Second: these are averaged, average statistical data, and focusing on them is not the most correct decision. Again, myelodysplastic syndrome is a disease, the treatment of which largely depends on the patient's faith in a better outcome.

Myelodysplastic syndrome is a group of pathological conditions accompanied by a violation of the hematopoiesis process. The disease leads to a change in the basic blood cells. Without therapy, there is a high risk of developing leukemia (blood cancer).

Myelodysplastic syndrome - what does it mean?

Myelodysplastic syndrome, MDS is a disease accompanied by impaired hematopoiesis of myeloid tissue. With the disease, there is a violation of the production of mature blood cells, as a result of which there is a deficiency of certain types. The blood cells themselves undergo modification and function poorly. The long course of the disease leads to the emergence of acute myeloid leukemia.

For ease of understanding of patients, MDS is often referred to by experts as preleukemia. In the medical literature of past years, you can find the terms "dormant leukemia" and "low-percentage leukemia", which well describe the clinical picture of this disorder. Such definitions are related to the level of blast cells in the patient's bone marrow. An excess of 20% indicates the presence of myeloid leukemia. If the concentration is less than the specified, the diagnosis of myelodysplastic syndrome is made.

Myelodysplastic syndrome - classification

Depending on the nature of the changes, the damaged cell type, the following types of MDS are distinguished:

1. Myelodysplastic syndrome, refractory anemia - lasts more than 6 months. When conducting a blood test, single blasts are recorded. Dysplasia of the erythroid lineage is found in the bone marrow.
2. Refractory cytopenia with multilinear dysplasia - characterized by the presence of single blasts, pancytopenia, an increase in the level of monocytes are recorded. In the bone marrow, less than 10% of the cells undergo changes.
3. Myelodysplastic syndrome with multilinear dysplasia - cytotpenia, without an increase in blast cells.
4. Unclassified myelodysplastic syndrome - characterized by cytopenia, the presence of single blasts. Their concentration does not exceed 5%.
5. Myelodysplastic syndrome with excess blasts - cytopenia without monocytosis, without an increase in blast cells in the peripheral blood.
6. Myelodysplastic syndrome associated with isolated 5q deletion - a form caused by a violation of the gene apparatus. The analysis traces anemia, thrombocytosis; the concentration of blasts exceeds 5%. An isolated deletion of the 5q gene is found on cytogenetic examination.

Causes of myelodysplastic syndrome

Often, specialists who have diagnosed myelodysplastic syndrome (MDS) fail to establish the specific cause of the pathology. In doing so, they always try to identify the root cause of the disease. Depending on this factor, it is customary to distinguish two forms of myelodysplastic syndrome:

1. Idiopathic (primary) - in most cases it develops for no apparent reason, in the absence of prerequisites.
2. Secondary - is the result of the presence of other pathologies (lymphoma, lymphogranulomatosis). In some cases, the pathology can be provoked by radiation or chemotherapy carried out the day before.

A number of studies conducted by oncologists have shown an increased likelihood of developing MDS in people with genetic abnormalities:

• neurofibromatosis;
• fanconi's anemia.

Primary myelodysplastic syndrome

The diagnosis of primary MDS is 80–90% of all cases of myelodysplastic syndrome. This type of pathology is more often recorded in patients of mature age, elderly people after 60 years. The doctors cannot unequivocally name the reasons for the development of pathology. At the same time, they identify a number of factors that increase the risk of developing MDS at times. Among those:

• smoking;
• living in areas with an increased radioactive background;
• harmful working conditions (constant contact with oil products, pesticides);
• congenital pathologies (Down's disease, Fanconi's syndrome).

Secondary myelodysplastic syndrome

Secondary MDS occurs in 10–20% of cases. Pathology occurs at any age. A common cause, doctors say, is the side effect of chemotherapy and radio waves. In addition, some drugs are capable of provoking changes in the blood picture:

• Cyclophosphamide;
• topoisomerase inhibitors (Topotecan, Irinotecan).

Myelodysplastic syndrome - symptoms

Symptoms and clinical picture of the disease directly depend on the degree of impairment, the stage of the pathological process. In some cases, an almost asymptomatic course is possible. In such patients, only during a routine examination, myelodysplastic syndrome is diagnosed as one of the signs of a blood disease. In this case, patients complain of the presence of nonspecific symptoms of pathology:

• weakness;
• fatigue;
• blanching of the skin;
• dizziness;
• fainting.

When myelodysplastic syndrome is accompanied by a decrease in concentration in the bloodstream, patients may experience periodic nosebleeds, profuse bleeding of the gums. Women may notice the appearance of menorrhagia - heavy periods. Bruises appear on the surface of the skin. MDS with a pronounced decrease in neutrophils and agranulocytosis is accompanied by the development of frequent colds, stomatitis. In severe cases, patients develop pneumonia.

Complications of myelodysplastic syndrome

Disruption of the hematopoietic system adversely affects the functioning internal systems and organs. A decrease in the concentration of red blood cells provokes the development of oxygen starvation. As a result of such changes, the first to suffer nervous system and the brain. However, the main complication that accompanies myelodysplastic syndrome, refractory anemia with an excess of blasts, is myeloid leukemia.

Pathology is characterized by the destruction of blood cells, is difficult to treat, often leads to the death of patients. The way out of the situation is allogeneic bone marrow transplantation. Other possible complications of MDS include:

• anemia;
• infectious diseases.

Myelodysplastic syndrome - diagnosis

Before diagnosing myelodysplastic syndrome, blood tests are performed repeatedly. A detailed study helps to establish which type of cells directly undergoes pathological changes. This information is used to prescribe a course of therapy in the future. A comprehensive examination of the patient should include:

1. Bone marrow examination - morphological examination of the aspirate, trepanobiopsy with histology.
2. Genetic test to identify possible chromosomal mutations (cytogenetic analysis).

Myelodysplastic Syndrome - Treatment

Treatment of myelodysplastic syndrome should be comprehensive. The tactics of therapy are determined by the clinical picture, symptoms, the nature of laboratory parameters. In the absence of signs of anemia, infectious pathologies, specialists take a wait-and-see tactic. In MDS with severe anemia, neutropenia, and thrombocytopenia, with an increased risk of leukemia, concomitant therapy is prescribed. In severe cases, it is indicated.

With late forms of the disease, pronounced clinic shows a course of chemotherapy. There are no generally accepted standards for this type of treatment. Experts are actively involved in the development of new drugs and drugs. In some cases, to stop the progress of the disease, to alleviate the patient's condition, they resort to immunosuppression.

How to treat myelodysplastic syndrome, what drugs, in what concentration to use - doctors determine individually.

1. Concomitant treatment is the most common treatment for MDS. It provides for frequent infusions of blood components.
2. Long-term use of this group of drugs can provoke an increase in the concentration of iron in the blood. To exclude such a possibility, chelators are prescribed at the same time, which bind iron and remove it from the body.
3. In the treatment of MDS in the absence of chromosomal mutations, immunosuppressants are used. They suppress the immune system, help to reduce the inflammatory process.
4. The impossibility of bone marrow transplantation is one of the indications for chemotherapy. High dosages of these drugs are used when myelodysplastic syndrome turns into or refractory anemia occurs (an increase in the concentration of blasts with hypercellular bone marrow).

Myelodysplastic syndrome - drugs

MDS treatment includes several areas. In the complex therapy of the disease, many drugs are often used. Among the main drugs:

1. Immunosuppressants - help to eliminate disorders in the immune system, which are manifested by the formation of autoantibodies, the development of autoreactive clones of T-cells. Representatives of this group: Cyclosporin, anti-thymocytic immunoglobulin.
2. Hypermethylation inhibitors - are prescribed for high-risk MDS, with a high concentration of blasts: Decitabine, Azacitidine.
3. Chemotherapy - it is used with an increased risk of transition to leukemia: Cytosar.
4. Thrombopoiesis stimulants - it is used with a pronounced decrease in platelet concentration, various bleeding: Romiplostim, Lonifarnib, Tipifarnib.

Myelodysplastic syndrome - alternative methods of treatment

Treatment of myelodysplastic syndrome with folk remedies does not bring results. The disease is difficult to respond drug therapy, therefore, doctors claim that there is no effect from the use of medicinal plants. Self-administration of folk remedies, decoctions, tinctures can adversely affect the patient's health.

Myelodysplastic Syndrome - Diet

There is no special diet for myelodysplastic syndrome. Doctors recommend compiling your menu, adhering to table number 15. The diet should have a caloric value of 3000 kcal, the volume of liquid should be 1.5–2 liters. The daily menu should contain the following foods:

• boiled eggs;
• cereals, pasta;
• vegetables and fruits, herbs;
• wheat bran;
• butter.