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Definitionã€‘ ã€myelodysplastic syndrome (myelodysplastic syndrome, MDS) is a group of clonal hematopoietic stem cell malignant disease, mainly for the sick and ineffective hematopoiesis, refractory cytopenia, high-risk acute leukemia to progress. Disease is more common in older people. Department of Hematology, General Hospital of Tianjin Medical University, the king of spring
MDS epidemiologyã€‘ ã€exact incidence is unclear. There are three possible reasons: â‘ MDS as a new understanding of the disease, until recently, into the International Classification of Diseases system, had registered the name of the non-standard, resulting in disease registers, death and other data confirm the poor reliability. â‘¡ MDS diagnosis difficult, particularly in the diagnostic criteria of low risk group great variation. Studies have found that dysplasia will also appear normal, many of whom are elderly and smokers. 50 years of age accounted for erythroid cell dysplasia 0.4% 7.6% 4.0% over the age of 50 to 28%; granulocytic dysplasia accounted for 3.0% ~ 12.5% and 6.0% to 29%. Dysplasia smoking can increase the proportion of 3.7%. â‘¢ part of the MDS patients without dysplasia.
British Leukemia Research Foundation in the mid-eighties of last century the population of Britain 1 / 4 of the epidemiological survey about the annual incidence of MDS 3.6/10 million. 90% of patients older than 55 years. Male: female was 1.4:1. After standardized male and female annual incidence rates were 4.69/10 and 2.51/10 million million. 75 to 79 years of age population, male and female incidence rates were 34/10 MDS million and 17/10 million. More than 80 years of age, the total incidence rate of 38.85/10 million men and women, respectively, and 28.37/10 61.72/10 million million. Increases with age, the incidence rate of rise. Followed by 54.7 million people in Dusseldorf group epidemiological surveys similar results with the British, MDS overall incidence of approximately 4.1/10 million, less than 50 years of age was 0.22/10 million, 50 to 69 years of age was 4.88 / 10 million, more than 70 years of age was 22.8/10 million. Sweden and France respectively, the incidence of 3.6/10 and 3.2/10 million million.
The past 20 years, MDS incidence is rising, in addition to improving the diagnosis, the chemotherapy drugs, car exhaust, pesticides, and nuclear radiation may be an incentive. Epidemiological studies clearly show that the UK MDS incidence increased year by year, million in 1984 to 2.38/10 to 4.59/10 million in 1993. Dusseldorf team from 1976 to 1980 showed the incidence of MDS was 1.3/10 million, and 1986 million in 1990 rose to 4.1/10.
MDS is the older of the most common blood system cancer, acute myeloid leukemia (AML) 3 times, chronic lymphocytic leukemia (CLL) and myeloma (MM) 2 times, than all of the non-Hodgkin lymphoma ( NHL) of the total incidence rate is still high. When more than 65 years of age, MDS has been higher than
ã€Etiology and pathogenesis is currently unclear leading cause of MDS. MDS incidence rise with age, suggesting that intrinsic factors that lead to aging of hematopoietic function in the pathogenesis of MDS work. Environmental and genetic factors also play a role. Application of cancer chemotherapy drugs are risk factors for genetic toxicity. Case-control studies have shown that Hodgkin's lymphoma (HD), NHL and other tumors were treated with alkylating agents, the incidence of secondary MDS and AML was significantly increased and peaked at about 5 years. More than 70% of secondary AML was observed in patients with dysplasia. Alkylating agent chemotherapy in the highest cumulative risk, and with the cumulative dose, chemotherapy, time, type and intensity of treatment related to alkylating agent. Radiotherapy also has a certain risk. Age above 40 years of age with relapsed or chemotherapy for a long time higher risk patients. Alkylating agent after treatment of the risk of secondary MDS in 10 years is 3% -4%, then decreased gradually. HD chemotherapy in patients with a strong cumulative risk rate can reach about 10%. Whether it is primary or secondary MDS, male incidence rates than women, which may be exposed to the environment in different ways or androgen stimulation of hematopoietic related. Splenectomy may lead to increased incidence of MDS.
Topoisomerase â…¡ inhibitors such as anthracyclines, table podophyllotoxin, etoposide also contributed to myeloid cancer risk factors. Some of these drugs is not a result of AML early MDS, occurs 1-3 years after treatment, may have abnormalities of chromosome 3. With different radiation and alkylating agents, topoisomerase caused more associated with 11q23 chromosomal translocations MDS. MDS secondary to other causes mostly 5 or chromosome 7 abnormalities.
Primary and secondary MDS in the common chromosomal abnormalities in the pathogenesis of the tips they have similarities. Although only less than 15% of MDS patients with previous history of application of cytotoxic drugs, but occupational or environmental exposure to potentially toxic drugs that can cause a genetic disease. Long-term exposure to benzene can lead to MDS, including myeloid, including increased incidence of cancer 5-20 times with the same alkylating agent, the incidence and intensity of contact time with a positive correlation. Epidemiological data show that other substances, such as solvents, petrochemicals and pesticides are risk factors for MDS or AML. Long-term case-control studies have also shown a lot of exposure to petrochemicals and solvents, the incidence of primary MDS was significantly increased. Smoking is a risk factor for MDS.
Gene result in reduced ability to detoxify chemical mutagen, which directly increases the susceptibility of different individuals MDS occur. Such as glutathione S transferase (GST) and glutathione can e-covalent DNA, the gene encoding the enzyme has a wide range of polymorphism, resulting in the enzyme function is also polymorphic. Case-control studies have shown that GSTÎ¸ bare naked type and GSTÎ¼ increased incidence of MDS type who can reach four times the normal. Bare-type GST lead to chemotherapeutic drugs and increased sensitivity to environmental toxicants. In addition, the microsomal epoxide hydrolase (HYL1) polymorphism increased and nicotinamide adenine dinucleotide phosphate quinine oxidoreductase (NQO1) polymorphism in lowering the incidence associated with AML. Therefore, the detoxification enzymes in congenital or acquired defects may increase the risk of MDS pathogenesis.
MDS patients with no family history of most adults, but also a lack of defined genetic susceptibility. MDS in 50 years of age is not a common disease, but 50 years of age is a genetic disease with multiple age. There are reports of 550 adult patients with MDS, 50 years of age account for only 7%. 14% of young patients with MDS family history, family history of high proportions of 35 times higher than older group. MDS in children are rare, of which 1 / 3 with a genetic susceptibility. The most common genetic disease is trisomy 21. Down syndrome children with acute megakaryocytic leukemia, the probability of 10-30 times higher than normal children, 1% of Down syndrome children with acute megakaryocytic leukemia. More than 50% of which occurred in children with early MDS, associated with chromosomal abnormalities such as +8 or -7. Other genetic factors include DNA repair defect syndrome Fanconi anemia, ataxia - telangiectasia, Bloom syndrome. Congenital diseases such as neurofibromatosis, congenital neutropenia, Kostmann agranulocytosis and Shwachman-Diamond syndrome are risk factors for MDS. Malignant transformation of Kostmann syndrome granulocyte progenitor cells in patients with G-CSF receptor mutation .
Pathogenesis of MDS has three characteristics: â‘ monoclonal hematopoiesis: interphase cytogenetics, X chromosome inactivation and allele polymorphism analysis confirmed that MDS progenitor cells derived from a variety of potential result of clonal expansion, this multi- progenitor cells into granulocyte, monocyte, red, megakaryocyte differentiation. Although the initial studies, MDS accumulation of B lymphocyte clone, but a recent study found the situation less. Monoclonal hematopoietic cell components has led to changes, such as hematopoietic cell membrane receptor, cell differentiation antigen abnormalities, abnormal enzymes in the cytoplasm and nucleus chromosome changes. Composition changes in turn led to cell differentiation, maturation and other functional abnormalities, such as the formation of a variety of hematopoietic cells caused by abnormal dysplasia and ineffective hematopoiesis. â‘¡ compromise immune function: its mainly in the immune system cells can not form for the MDS monoclonal sufficiently effective immune surveillance and immune clearance, leading to the proliferation of cells in MDS monoclonal. The reason may lead to cloning of MDS bone marrow injury while changing the factors of lymphocyte function or lymphocyte cell lines but also lines from higher stages of MDS clone related. â‘¢ becoming cancer prognosis. MDS monoclonal cell immune function by the end of three. One case is immunocompromised, MDS clonal cells have a proliferative advantage, and gradually into cancer; a situation with MDS clonal cell immune function in equilibrium, MDS clone in a very long time do not develop into leukemia, but the MDS clone persist and continue to attack the immune system, resulting in reduced blood cells, resulting in various complications, the patient died before changing to leukemia; the third case of the immune system to effectively remove the MDS clone, the patient was healthy performance, current technology can not This situation is detected .
Clinical manifestationsã€‘ ã€MDS clinical manifestations were symptoms and signs of reduced blood cells. Most patients have anemia, manifested as pale, fatigue, reduced endurance, angina, and dizziness. Some patients with infection or bleeding. MDS patients vulnerable to infection because on the one hand, leukopenia with the other, with the white blood cell function defects. Found that leukocyte chemotactic function in patients with MDS and microbial killing function obvious abnormalities. Parts of a common bacterial infection of the skin and respiratory tract. Infection can also be hidden there, for the poor response to antibiotic treatment. Infection is the main cause of death in patients with MDS. Fungi, viruses, and incidence of mycobacterial infection in the use of systemic immunosuppressive agents or cytotoxic drugs will be significantly increased after treatment. MDS patients with a variety of hemorrhagic manifestations can occur, such as skin and mucous membrane bleeding, nose bleeding, gum bleeding, menstrual increase, serious bleeding may occur in vital organs, such as gastrointestinal bleeding, respiratory tract bleeding, and even cerebral hemorrhage, is MDS patients led to the death of another main reason. In addition to CMML, the liver, splenomegaly and enlarged lymph nodes are uncommon. Pleural effusion can occur in some patients, pericardial effusion or ascites.
ã€Featuresã€‘ 1 pathological laboratory blood hematopoietic system performance was diversity of MDS, the most characteristic is that there are at least a series of dysplasia. Most patients with MDS associated with anemia, there is no corresponding increase in reticulocytes. Greater than 50% of MDS patients when treatment pancytopenia, other patients or two lines for a series of blood cells decreased. Less than 5% of the patients is not associated with anemia.
Red blood cell morphology is usually normal or large cell, part of the RARS for small cell or low-pigmented cells of different sizes. The most common form of abnormal red blood cells is a huge oval, and other abnormalities, including oval-shaped red blood cells, tear drop-like red blood cells, red blood cell debris, lip-shaped cells and spiny cells. Can also occur in peripheral blood basophilic stippling, Howell-Jolly bodies and the kind of change megaloblastic nucleated red blood cells. Erythroid marrow dysplasia in the nuclei include megaloblastic degeneration, nuclear budding, internuclear bridges, multi-core, such as nuclear fragmentation and cytoplasmic changes include fine particles of iron ring, cavity formation, and PAS-positive and so on. Erythroid dysplasia is a more meaningful indicator of the phenomenon of nuclear abnormalities, such as multi-core, such as the odd loose nuclear and chromosome.
50% of MDS patients with neutropenia at diagnosis, mainly neutropenia based. Immature granulocytes in peripheral blood can be seen. If Auer should be diagnosed as RAEB-t. The most common change in granulocyte nuclear lobulation reduce that "bogus Pelger-Huet" deformity. Cytoplasmic granules reduced or absent. Nucleus was circular or bar, secondary MDS are more common. Even can see the "false Chediak-Higashi" bone deformities and congenital agranulocytosis like morphology. Myeloid peroxidase and alkaline phosphatase activity decreased, increased monocyte specific esterase. Neutrophil phagocytosis, bactericidal, adherence and chemotaxis dysfunction, reduced resistance to bacterial infection. This anomaly more common in patients with deletion of chromosome 7.
25% MDS patients at diagnosis have different degrees of thrombocytopenia, but simply thrombocytopenia are rare. 5q-syndrome, there may be thrombocytosis. Large platelets, megakaryocytes leaf poor is a common form of abnormal common megakaryocyte morphologic abnormalities, including lymphoid Small megakaryocyte, a single round of nuclear giant cells and multiple round nuclear megakaryocytes and megakaryocyte granules and reduction.
Not only CMML appears mononucleosis, other types of MDS often appear higher proportion of mononuclear cells. However, many requirements CMML monocytes absolute 1 Ã— 109 / L, and often accompanied by an increase in granulocytes. Bone marrow hyperplasia was active, with marked hyperplasia of granulocytes active part both in the promyelocytic cells and monocytes morphological characteristics.
2 bone marrow biopsy in pathological diagnosis and prognosis of MDS has important value. It can not only determine the degree of proliferation of bone marrow and found that abnormal bone structure, but also to rule out pathological causes of lymphoma and metastatic carcinoma of blood. Most MDS patients with bone marrow biopsy showed active bone marrow hyperplasia or obvious, a small reduction for the proliferation, suggesting that blood cells decreased mainly due to ineffective hematopoiesis. Bone marrow biopsy specimens in the original myeloid or promyelocytic clusters located in the central part of the bone marrow, blood vessels away from the trabecular bone structure and endosteal surfaces, this is called "abnormal localization of immature precursor cells" (ALIP). There is a part of 3 or more than 3 ALIP phenomenon, known as the "ALIP positive." ALIP common in RAEB patients. If other types of MDS appears ALIP phenomenon, and more tips soon progress to acute leukemia. Bone marrow biopsy for the low proliferative MDS, MDS with myelofibrosis has an important role in the diagnosis, the other, pathology for the determination of megakaryocytes is also a valuable reference.
3 in MDS cytogenetic cytogenetic diagnosis, prognosis and pathogenesis play a very important role. Conventional karyotype detected 40-70% of primary MDS and 95% of secondary MDS have clonal chromosomal abnormalities. Common in primary MDS cytogenetic abnormalities occur in 8,5,7, Y, 17 and 20 chromosomes. Secondary MDS and more complex karyotype changes. Studies have found that with the increase of the degree of risk MDS, the incidence of chromosome abnormalities increased. Subtypes incidence of abnormal karyotype RA (24%), RARS (29%), RAEB-1 (35%), RCMD-RS (37%) and RAEB-2 (38%). If the morphological characteristics consistent with MDS, associated with chromosomal abnormalities, the strong support for the MDS diagnosis. Recent studies have found that chromosomal abnormalities may precede morphological changes appear. In view of prognosis and chromosomal abnormalities in MDS to white in the importance of the International Prognostic Scoring System (IPSS) and so the chromosomal abnormalities in an important position.
4 hematopoietic stem cell in vitro MDS patients in vitro stem cell culture often appear leukemia-like growth pattern, CFU-GEMM, BFU-E, CFU-E, CFU-GM, CFU-MK colony formation in reduced or no growth, cFU -GM set of clusters increased, colony / cluster reduction in the proportion set.
5 MDS clone phenotype abnormal expression of cell surface differentiation antigen, immunophenotyping for the diagnosis of dysplasia is not obvious MDS has important reference value. CD34 cells (CD33 CD13) / CD15 + ratio test can help determine the state of myeloid cells, for diagnosis and classification are also a valuable reference. It should be noted when bone marrow derived, it is often mixed with varying amounts of blood, CD34 cells, the results may not be entirely in line with the bone marrow. In addition, not all of the original cells are expressed CD34, CD34 cells therefore can not be fully equivalent to the original cell, diagnosis and classification can not be used when the percentage of CD34 cells instead of the original cell percentage.
ã€Classification and diagnosis of peripheral blood and bone marrow, according to secondary unexplained or three RCMD, FAB cooperative group will be divided into five subtypes of MDS, refractory anemia (RA), RA with ring sideroblasts promyelocytic ( RARS), RA with blasts type (RAEB), transformed RAEB (RAEB-t) and CMML. Although the FAB classification there are many problems, but its repeatability is good, is still widely used. 1640 cases reported in the literature according to FAB classification of MDS patients, 346 patients (21%) of RA, 303 patients (17%) as RARS, 219 patients (13%) CMML, 614 patients (37%) as RAEB, 159 cases ( 12%) as RAEB-t. Although widely used, but some still can not be applied in patients with MDS FAB classification criteria. This therapy-related MDS is particularly obvious. Such cases include unclassified MDS (MDS-U) or refractory cytopenia with multilineage dysplasia (RCMD).
CMML monocytes than 1000/ul, or Department of a series of bone marrow dysplasia; peripheral blood progenitor cells no more than 5% bone marrow blast cells less than 20%. For the MDS, including CMML whether there has been dispute as CMML and chronic myelogenous leukemia with (CML) myeloproliferative disorders similar characteristics. Retrospective study in patients with Ph chromosome negative CML, many patients meet the diagnosis of CMML and other MDS, molecular monitoring of BCR / ABL fusion gene and fluorescence in situ hybridization (FISH) is the basis for identification of the two.
FAB classification criteria have obvious defects, such as anemia itself does not have the characteristic morphological characteristics, RA does not apply to the main grains, abnormal megakaryocyte MDS patients. Recently, WHO proposed a new classification standard . New standard that only a series of abnormalities can be diagnosed as MDS, and in accordance with the scope of developmental abnormalities and the number of primitive cells in the establishment of new subtypes. RAEB-t subtypes abolished, its classified as AML. 5q-syndrome subtype is proposed to describe patients with deletion of chromosome 5q31-33. Single non-MDS erythroid abnormalities can not be classified as MDS. Retrospective application of the standard WHO classification results show that, WHO standard is more accurate in prognosis, but not as good as the Joint International Prognostic Scoring System FAB (IPSS). WHO classification criteria proposed a new classification of myelodysplastic / myeloproliferative disease syndrome, developmental abnormalities have used to describe both the proliferation of bone marrow diseases, including CMML, atypical CML, juvenile myelomonocytic leukemia (JMML). Diagnostic criteria for CMML need white blood cell count greater than 13000/ul. According to the percentage of primitive cells and eosinophilia are further divided into three subtypes. The third type of characteristic appear on the chromosome 5q-platelet-derived growth factor (PDFG)-Î² receptor gene rearrangement, resulting in constitutive receptor activation.
Patients sustained unexplained cytopenia or mononucleosis should be considered when the possibility of MDS. Should be detailed history and physical examination, especially if used anticancer drugs and radiation therapy, MDS / AML family history, history of recurrent infection or bleeding, is there pale, infection, bruising and splenomegaly and so on. Should be combined with blood, bone marrow smear, iron staining, such as biopsy and chromosome examination. Careful examination of peripheral blood and bone marrow cell morphology whether there is dysplasia. Dysplasia is not necessarily exist MDS, need to be further exclusion of other diseases that can lead to dysplasia, such as megaloblastic anemia, immune related pancytopenia, paroxysmal nocturnal hemoglobinuria, HIV infection, tuberculosis and alcoholism . RBC folate and plasma vitamin B12 levels checked help megaloblastic anemia other than. Autoimmune targets, PNH clone detection for identifying an important role in MDS. CMML need to detect whether there is 5q31-33 translocation induced PDGFRÎ² gene rearrangement. Sometimes, the necessary experimental treatment (such as raw materials or additional blood immunosuppressive therapy) on the differential diagnosis of MDS is also very important. In summary, MDS diagnosis should be based on whether there is abnormal clonal hematopoiesis (hematopoietic dysplasia and ineffective hematopoiesis abnormal clone is part of the performance), and excluding other diseases. Diagnosed with MDS and then according to standards or WHO standard FAB classification. Development perspective, according to WHO standard classification is appropriate.
ã€‘ ã€Differential diagnosis
1, immune related pancytopenia blood of three lines or two lines, a series of blood cells reduced, but the reticulocyte or (and) the percentage of neutrophil is not low; bone marrow erythroid or (and) granulocyte percentage is not low, or megakaryocyte number, is easy to see erythropoiesis Island, or bloodthirsty phenomenon. Autoantibody-positive bone marrow cells. Adrenocorticotropic hormone and (or) high dose intravenous immunoglobulin treatment is effective (from the blood transfusion and one or two lines or three lines have different blood cell recovery).
2, aplastic anemia, pancytopenia, reticulocyte percentage and absolute values were reduced; liver and spleen is not; bone marrow hyperplasia at least one part to reduce or severe reduction (such as hyperplasia, there must be significantly reduced hematopoietic cells, non-hematopoietic cells was increase), bone marrow particles empty, bone marrow biopsy showed reduced hematopoietic tissue, adipose tissue increased; can cause pancytopenia than other diseases.
3, paroxysmal nocturnal hemoglobinuria is acquired defects in blood cell membranes caused by abnormal sensitivity of complement activation as a hemolytic disease. Performance and sleep may be related to intermittent episodes of hemoglobinuria, pancytopenia, or repeated thrombosis. CD55 and CD59 on hematopoietic cell deficiency. In some cases (red lines can be developed to the PNH clone in peripheral mature red blood cells) acid hemolysis and sucrose hemolysis, venom factor hemolysis test and urine hemosiderin positive and in some cases can only be measured with blood cell membrane GPI anchored protein PIG-A gene deletion or exception.
4, other diseases, tuberculosis, HIV infection and arsenic poisoning are apparent such as dysplasia, to go through medical history, physical examination and relevant laboratory tests were identified.
ã€Treatmentã€‘ MDS treatment should be based on IPSS risk classification based on the patient's age, physical condition and the wishes of patients with individual treatment options. And Int-â… low-risk patients to improve symptoms due to reduced blood cells and improve the quality of life based, and Int-â…¡ and high-risk were managed with removal of malignant clone, normal polyclonal hematopoietic reconstruction and prolong survival time as the main target. Important part of old age or organ dysfunction combination Int-II high-risk MDS patients can only improve the quality of life and prolong survival time as the main treatment goal [5-7].
1, support the treatment of the current standard treatment for MDS remains supportive care. Supportive care, including regular monitoring of patients, psychosocial support, quality of life assessment. Patients with obvious symptoms of anemia and red blood cell (preferably to the white blood cells), severe thrombocytopenia or bleeding due to thrombocytopenia, platelet transfusion caused. For the planned transplant patients, infusion of blood products should be irradiated. Platelet transfusion refractoriness or severe thrombocytopenia, the can be applied aminocaproic acid and other anti-fibrinolytic drugs. Neutrophils to be lower to prevent and control the infection.
2, although the high specificity of the treatment of iron overload treatment can reduce the number of red blood cell transfusion, but ineffective treatment in some patients, requiring long-term infusion of red blood cells and lead to iron overload. Therefore, to effectively deal with the resulting treatment of iron deposition is an important aspect of MDS. Through a large number of red blood cell transfusion in patients on long-term (such as thalassemia, MDS) study of chronic iron overload has been clearly the pathophysiological process and on the liver, heart and endocrine toxicity. When more than transferrin plasma iron binding capacity, non-transferrin bound iron (NTBI) increases, with oxygen and oxygen combine to form hydroxyl radicals, lipid peroxidation, cell membrane, proteins, DNA and organ damage. Patients with MDS and thalassemia iron chelation therapy studies have shown that iron chelators can prevent and reverse the damage caused by high load of iron. For the past existence of cardiac function in patients with liver dysfunction, or to iron therapy is particularly important. For the past number of RBC units or more, or is expected to reach 20-40 to red blood cell or serum ferritin is greater than 2500mg / L in patients, the proposed application to ferric ammonium treatment. To iron therapy in patients with mostly low-risk patients, a relatively long duration, large number of red blood cell transfusion. For combined with cardiac or liver dysfunction in patients as early as possible to iron treatment should be. Course of treatment requires monitoring of serum iron concentration, it decreased to 1000mg / L or less. Superconducting quantum interference device (SQUID) and MRI detection sensitivity for the monitoring of iron overload than serum iron concentration. Therapeutic dose of iron to ammonium 1-2mg, evening subcutaneous injection 5-7 times per week. Ferric ammonium due to the short half-life is not recommended for intravenous drug use. Medication should be monitored regularly during the eyesight, hearing and renal function. Take a long time due to subcutaneous administration of ammonium iron, oral iron chelator more easily be accepted, the current type of drugs Ferriprox and ICL670.
3, hematopoietic cytokines for symptoms associated with reduction of blood cells in patients with refractory, consider the application of cytokines. Such as repeated infections or difficult to control infection, can be applied to recombinant human granulocyte colony stimulating factor (G-CSF) or granulocyte - monocyte colony stimulating factor (GM-CSF); with obvious symptoms of anemia can be applied to erythropoietin hormone (EPO).
EPO Â± G-CSF can increase the hemoglobin concentration in some patients and reduce the number of transfusions. RA and RAEB patients, if symptoms of anemia, serum EPO level of less than 500U / L, need for blood transfusion less (not more than 2 units per month), can be applied to rHu EPO treatment ,150-300U / kg / d, sc ,2-3 months. For an invalid patients, can be added with rHu G-CSF ,1-5ug / kg / d, subcutaneously ,2-3 months, so that white blood cells maintained at 6-10 Ã— 109 / L. If invalid, disable cell factor; if effective, can be tapered to maintain a stable hemoglobin level.
For symptoms of anemia, serum EPO level of less than 500U / L, need for blood transfusion less (not more than 2 units per month) of the RARS patients, can be applied to rHu EPO United rHu G-CSF treatment, rHu EPO 150-300U/kg / d, subcutaneously; rHu G-CSF ,1-5ug / kg / d, subcutaneously ,2-3 months. If invalid, disable cell factor; if effective, can be tapered to maintain a stable hemoglobin level.
Serum EPO levels greater than 500U / L in patients on EPO and G-CSF treatment response is poor, not recommended.
4 low-intensity treatment of low-intensity treatment, including low-intensity chemotherapy, farnesyltransferase inhibitors, anti-angiogenic drugs.
Low-intensity chemotherapy drugs are small-dose cytarabine, a small dose of melphalan, 5 - azacytidine. Past that the treatment of MDS with low-dose cytarabine induction of differentiation, is still currently considered the main role of cytotoxicity. Small dose of melphalan can be used for older, high-risk MDS patients. 5 - azacytidine (azacytidine) is methyltransferase inhibitors, can reduce the risk of leukemic transformation, improved quality of life of patients and prolong survival. Around 60% efficiency. Mainly for the relative risk of progressive and MDS. Specific Usage is: 75mg/m2/d, subcutaneously, for 7 days, a course of a month, a total of 4-6 courses. The drug is already FDA-approved for the treatment of MDS. Decitabine (5 Miscellaneous -2 deoxycytidine) is a methylation inhibitor. The treatment of MDS total effective rate was 49%, 64% of high-risk group can be achieved, about 30% of patients had cytogenetic remission.
Farnesyl transferase inhibitors (FTI) <20% of MDS patients with RAS oncogene mutations. RAS gene superfamily encoding GTPase, GTPase is a signal transduction, cell proliferation and maintenance of malignant phenotype of the key regulators of ingredients. Farnesyltransferase are Ras-GTPases post-translational modification of the first enzyme, but also the rate-limiting enzyme. Tipifarnib (R115777, Zarnestra) and lonafarnib (SCH66336, Sarasar) is the completion of Phase II clinical trial of the FTI drug. 98 patients with advanced MDS and AML is not suitable for chemotherapy in elderly patients Tipifarnib results show that the effective rate was 44%, CR 21%, treatment-related mortality rate was 7%. Lonafarnib II clinical trial showed erythroid response rate was 35%, platelet response rate was 22%, 43% of patients less than 50% of the original cells. The main side effects are diarrhea and hypokalemia. The progress of such drugs may become the treatment of MDS and AML effective older drugs.
Anti-angiogenic drugs thalidomide has antiangiogenic properties and inhibition of tumor necrosis factor, is the first trial of similar drugs in the treatment of MDS. Nerve drug toxicity, low efficiency. Lenalidomide (CC-5013/Revlimid) is a derivative of thalidomide, no neurotoxicity. It is a ligand-mediated cell response modifiers, including enhanced antigen in the starting role in the immune response, regulation of integrin affinity, inhibition of angiogenesis nutrition, and enhance the original cells to erythropoietin response. In Phase I clinical trial, 24/36 patients with effective, 21/36 from blood transfusion. Effects associated with the chromosome, 5q31.1 deletion rate was 91% in patients with normal karyotype, 68% to 17% of other patients. IPSS low-risk group was 72%, 25% of high-risk group. Karyotype analysis 65% of patients with cytogenetic response occurred, abnormal mitosis by 50% or more. 67% of complete remission, mainly in patients with 5q31.1 deletion. Remission lasted longer, with a median follow-up time of 81 months, the median time from transfusion to 48 weeks. Neutropenia, thrombocytopenia is the most common side effects were dose dependent, 61% of patients having withdrawal or reduction. Lenalidomide may be effective therapy for MDS 5q31.1 deletion.
Trioxide can be covalently bound and depleted cells, thiol-rich proteins such as glutathione, and has anti-angiogenic properties. It inhibits glutathione peroxidase, the peroxide production increased destruction of mitochondrial respiration and mitochondrial membrane integrity, inhibition of anti-apoptotic protein, caspase-mediated apoptosis start reaction. In MDS and AML, VEGF-A also inhibited the proliferation of original, direct effect on endothelial cells of neovascularization. Three clinical trials showed that 20-25% of its efficiency, but little or no complete remission and partial remission.
5 high-intensity treatment, including treatment of high-intensity chemotherapy and strongly induced hematopoietic stem cell transplantation. Although high-intensity treatment of large chance of changing the natural course, but treatment-related mortality.
Compared with primary AML, MDS and MDS associated AML complete remission rate with standard chemotherapy, bone marrow suppression and long, short remission, relapse rate, high mortality during chemotherapy. This may be related to two factors, first, the majority of MDS patients are older, second, MDS stem cell and bone marrow stromal cells have a completely different biological characteristics of AML (including a poor prognosis karyotype, early stem cell phenotype, and more increased expression of drug resistance mark). Recent results show that the current application of several strong chemotherapy (Idarubicin Cytarabine, fludarabine cytarabine, topotecan cytarabine) in effect no significant difference However, traditional chemotherapy than other AML program is effective.)
Hematopoietic stem cell transplantation
HLA matched sibling donor transplantation in MDS patients with disease-free survival rate (DFS) 29-40%, 37-50% of non-relapse mortality, relapse rate of 23-48%. The effect of graft factors were age, time of onset, disease status, number of bone marrow blast cells, chromosomal abnormalities, stem cells, to T, donor type and conditioning regimen. The results show that bone marrow transplantation in Europe as treatment-related mortality (TRM) decreased after the transplant in 1989, DFS and OS were 3-year increase. Seattle reported using busulfan conditioning regimen and maintain it in the blood can increase the concentration in the 800-900ng/mL transplant patients. Use of GCSF-mobilized peripheral blood stem cells as a source of stem cells for transplantation, implantation was significantly lower than the probability of failure of bone marrow stem cells, and have a strong graft-versus-MDS effect. Neutrophil and it can shorten the duration of thrombocytopenia, the TRM down. Low-risk MDS program used myeloablative low recurrence rate, long-term DFS> 50%. The best time to transplant MDS is unclear. CMML associated with the original cells> 5%, neutrophils> 16 Ã— 109 / L, monocytes> 2.6 Ã— 109 / L with poor outcome, should be selected transplant. Transplant 2 years DFS was 18% and the recurrence rate was 42%. Data from several research groups have confirmed the age and stage of the OS, DFS and relapse rate of independent prognostic significance. Young and low-risk is a good prognostic factor. Chromosomal abnormalities is an important factor in the effect of transplantation. Complex chromosome 7-year recurrence rate of up to 87%. IPSS high-risk, medium risk and low risk group were 6% EFS, 40% and 51%, recurrence rates were 82%, 12% and 19%. France transplantation tMDS / AML 2 years EFS, relapse rate, TRM were 28%, 42% and 49%. Although the removal of T lymphocytes decreased TRM, but increases the relapse rate, little effect on the efficacy of transplantation.
Non-myeloablative conditioning regimen (RIC) of the main principle is to reduce the toxicity of myeloablative related programs, the use of lymphocyte infusion graft-versus-MDS effect. RIC to a large extent dependent on the strong inhibition of immune receptor, in order to facilitate graft implantation and the establishment of full donor chimerism type. Kr
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(1) acute leukemia
Acute leukemia is a group of primary hematopoietic tissue malignancies, characterized by bone marrow and other hematopoietic tissues in a wide range of leukemic cells in the abnormal proliferation and infiltration of other tissues and organs, leading to normal hematopoietic failure, showed a significant reduction in normal hematopoietic cells . The main clinical manifestations were fever, bleeding, anemia, liver, spleen, lymph nodes. Generally believed that the incidence of this disease with ionizing radiation, certain chemicals, drugs, viruses, and genetic factors, but also by the state and humoral immune factors, leading to hematopoietic cells become malignant, uncontrolled proliferation of malignant cells in leukemia and bone marrow infiltration other organizations, and ultimately caused a significant reduction in normal hematopoietic cells, there can not control the bleeding and infection and death. We are from the clinical point of view, this disease is divided into acute lymphocytic leukemia and acute non-lymphocytic leukemia into two categories, then divided each of the subtypes.
(2) acute lymphoblastic leukemia (ALL), according to cell morphology and different clinical outcomes, will ALL be divided into L1, L2, L3 are three subtypes.
L1 type: mainly small lymphocytes, little cytoplasm, high nucleus, cytoplasm ratio, nuclear shape rules, uniform and compact chromatin, nucleolus is not clear.
L2 type: Most cell volume is 2 times the small lymphocytes, some significant heterogeneity in cell size, cytoplasmic moderate basophilic, chromatin showed diffuse fine or dense block, clear nucleoli, one or more.
L3 type: the uniform large cells, abundant cytoplasm, deep basophilic, containing most obvious bubble chamber, nuclear round, thin and dense chromatin, the nuclear two clear, one or more.
The classification and clinical prognosis of, L1-based model better prognosis than L2, L3 type difficult to be alleviated, and poor prognosis.
(3) acute myeloid leukemia (AML) AML clinical will be divided into 7 subtypes.
M1: (very derivative of acute myeloid leukemia primitive type) since the original undifferentiated or poorly differentiated myeloid hyperplasia is characterized by primitive myeloid sub-â… and type â…¡. The cytoplasm of type â… no particles; â…¡ type of cytoplasmic granules containing a small number of addicted to Azure or Aoer bodies. The original grain type â… Type â…¡ â‰¥ 90%, promyelocytic ~ mature granulocytes, monocytes below 10%.
M2: (Part of differentiated primitive acute myeloid leukemia) is divided into two subtypes. â‘ M2a, the bone marrow myeloblast cells> 30%, monocytes <20%, promyelocytic the following phases> 10%; â‘¡ M2b bone marrow abnormalities of the original early promyelocytic cells increased to abnormal neutral in promyelocytic proliferation based, such cell> 30%.
M3: (acute promyelocytic leukemia) cells with abnormal proliferation of promyelocytic based, often> 30%, divided into two subtypes, M3a coarse particle type, M3b for the fine particle type.
M4: (acute myeloid, monocytic leukemia) This type of bone marrow and peripheral blood by varying the proportion of granulocyte and monocyte lineage cells, is divided into four subtypes: â‘ M4a to the original cells and promyelocytic hyperplasia Lord of the original, young single and monocytes> 20%; â‘¡ M4b to the original, young single and mononuclear cell proliferation mainly original and promyelocytic> 20%; â‘¢ M4c primitive cells with both myeloid, but also has monocyte Department of Morphology by> 30%; â‘£ M4eo addition to the above characteristics, there are thick, round eosinophilic granules, eosinophil darker colored 5% -30%.
M5: (acute monocytic leukemia), Department of bone marrow mononuclear cells â‰¥ 80%, including the original single-core, immature and mature mononuclear mononuclear cells were divided into two subtypes. â‘ M5a (undifferentiated type) the original single-core> 80%. â‘¡ M5b (Part differentiated) progenitor cells and immature monocytes> 30% of the original single-core "80%.
M6: (acute leukemia) in erythroid precursor cell proliferation, accompanied by pathological blood and bone marrow characterized by an increase in the number of primitive cells, nucleated red blood cells> 50% of the original or the original immature granulocyte single> 30%, blood film the original grain or 75% of the original single cell.
M7: (acute megakaryocytic leukemia) bone marrow or peripheral blood of the original immature megakaryocyte â‰¥ 30%, divided into 2 â‘ undifferentiated, bone marrow Central Plains megakaryocytes> 30%, â‘¡ differentiated, bone marrow and external blood to a single round the nuclear core and multi-round main pathological megakaryocytes.
(4) special types of acute leukemia
â‘ The proliferation of acute leukemia: peripheral blood showed pancytopenia, and occasionally the original cells, generally without the liver, splenomegaly, bone marrow hyperplasia reduced nuclear cells decreased immunogenicity cells> 30%, lower proliferation of bone marrow biopsy.
â‘¡ adult T lymphoblastic leukemia, a superficial lymph nodes, peripheral blood polymorphonuclear cells accounted for 10% or more, is a T cell type.
â‘¢ plasma cell leukemia: peripheral blood plasma cells> 20% or absolute value of â‰¥ 2.0 Ã— 109 / L; bone marrow proliferation of plasma cells was the original and immature plasma cells increased significantly, with abnormal morphology.
â‘£ mast cell leukemia: clinical with leukemia or the performance of mastocytosis, lymph node, liver, or splenomegaly, peripheral blood mast cells, bone marrow, as evident in the proliferation of mast cells, possession of more than 50% of cells; urine histamine increased.
â‘¤ eosinophilic leukemia, eosinophils in blood was significantly increased and sustained, the majority of up to 60%, abnormal naive eosinophils, bone marrow eosinophilia, abnormal shape, left shift, how the stage of immature eosinophils.
â‘¥ basophil leukemia, blood basophil in significantly increased, differences are naive basophil, the bone marrow can be a lot of immunogenicity basophil granules> 5%, basophils early, middle and late promyelocytic also increased, with a left shift phenomenon.
â‘¦ mixed cell leukemia, refers to the myeloid leukemia cell lines and lymphocytes in the series involving a group of common diseases. Expressed by cells of different origin and can be divided into 3. a. Double the performance of leukemia, each cell can express both myeloid cell lines and cell line characteristics. b. Double clonal leukemia, leukemia cell heterogeneity, part of the expression of myeloid cell line characteristics, the other part is the expression of lymphocyte cell lines features. c. double-series type of leukemia, and the cloning of leukemia similar to the double, but the two parts of leukemia cells from the same pluripotent stem cells.
â‘§ central nervous system leukemia, 1) signs and symptoms of central nervous system, 2) cerebrospinal fluid changes in leukemia cells seen in smears, and 3) exclusion of other causes similar central nervous system or cerebrospinal fluid changes.
(5) chronic leukemia
â‘ chronic myeloid leukemia (CML), CML is a pluripotent stem cell mutation caused by a clonal disease, to mature granulocytes and their precursors, including granulocytic, monocytic, erythroid and megakaryocytic cell lines and some B lymphoid cell lines characterized by proliferation and accumulation. According to the clinical progression in three stages: chronic phase, accelerated phase, blast phase.
â‘¡ chronic lymphocytic leukemia (CLL), CLL is a kind of blood, bone marrow, lymph nodes, liver, spleen, and other mature tube characterized by lymphocyte proliferation and accumulation of the highly variable disease. T cell type and clinical type B cells in two.
(6), myelodysplastic syndrome (MDS)
MDS is an abnormal proliferation and differentiation of hematopoietic stem cell syndrome. It is characterized by anemia, may be associated with infection or bleeding, blood showed pancytopenia, or any department or secondary pancytopenia, bone marrow showed hyperplasia or apparent active proliferation of a few can also be decreased. Three-line blood cell dysplasia significantly, the original grain or promyelocytic increase, but to achieve the diagnostic criteria for acute leukemia, the disease also known as? Quot; preleukemia. "Unknown cause of primary MDS, secondary MDS and Some blood plasma, and other factors received chemotherapy, the bone marrow hematopoietic stem cells are malignant clonal growth, bone marrow hematopoiesis in an invalid state. The bacteria are divided into five subtypes
â‘ refractory anemia (RA)
â‘¡ with ring sideroblasts refractory anemia increased (RAS)
â‘¢ refractory anemia with blasts (RAEB)
â‘£ blasts in transformation of refractory anemia (RAEB-t)
â‘¤ CML - monocytic leukemia (CMML)
Category (a) cause categories can be divided into primary and secondary health (secondary to long-term chemotherapy, radiotherapy, or secondary to cancer, autoimmune disease, etc.) (b) morphological classification of hematology and bone marrow morphology according to characteristics, FAB MDS Cooperative Group will be divided into 5 types, various features are as follows: 1. refractory anemia (RA) mostly occurs in elderly patients aged over 50, the main clinical, anemia, decreased reticulocytes, peripheral blood neutrophil and platelet are mostly reduced. Peripheral blood progenitor cells rare, not more than 1%. Proliferation of normal bone marrow cells or hyperactivity, and more obvious erythroid hyperplasia, a rare ring sideroblasts, red blood cell morphological abnormalities more common. Granulocyte and megakaryocyte has some form of abnormal cells, but usually less severe. The original bone marrow
Abnormal cells in hematopoietic stem cells no more than 5%. 2. Refractory anemia with ring sideroblasts granulocyte (RAS) This group of patients with RA appears the main difference is that the ring sideroblasts, bone marrow nucleated red blood cells account for more than 15%. The majority of white blood cells and platelet count normal, serum ferritin concentration increased. 3. Refractory anemia with blasts (RAEB) patients were older, most of them in 50 years of age. Most three-line cells in peripheral blood were reduced to varying degrees, a few cases only two lines were reduced. Three-line cells were markedly abnormal. Peripheral blood progenitor cells often appear, but no more than 5%. Primitive bone marrow cells between 5% to 20%. Immature myeloid and erythroid cells increased, significant morphological changes. 4. Chronic myelomonocytic leukemia (CMML) are more seen in the elderly. Liver, splenomegaly common. Anemia and thrombocytopenia. The main feature is more blood and bone marrow mononuclear cells. Peripheral blood mononuclear cells in the absolute number of 1 Ã— 109 / L, often accompanied by an increase in neutrophils, and morphologic abnormalities. Primitive cells in peripheral blood of less than 5%. Bone marrow cell proliferation was significantly increased grain: red ratio increased, the original cells in 5% to 20%. Three-line cells can be significantly abnormal morphology. 5. Refractory anemia with excess blasts type transformation (RAEB-T) patients are over the age of 50, but not uncommon in young adult domestic coverage. Liver and spleen not enlarged. RAEB blood and bone marrow in addition to a number of changes, often the following characteristics: â‘ the original peripheral blood cells> 5% but not more than 20%; â‘¡ primitive bone marrow cells in more than 20%, but less than 30%; â‘¢ primitive cells Auer bodies are visible; â‘£ 50% of the patients evolved to acute leukemia, the patient survival time is short, most not more than one year. (C) WHO Classification (2000 Revision): In recent years, with cytology, immunology, genetics and molecular biology and its application in the rapid development of MDS diagnosis, classification, staging and prognostic applications, MDS classification system has been improved gradually, since 1995 WHO classification of MDS, an amendment made in 2000. The classification is as follows: MDS by the FAB classification criteria has been the transition to the WHO standard. Each department to determine whether abnormalities of other cells â‰¥ 0.10, the lowest so far no generally accepted morphological diagnostic criteria for MDS, there are difficulties in determining the diagnosis of RA patients should be regularly followed up. Etiology and pathogenesis of MDS, but the primary, that is, for unknown reasons. Or had chemical carcinogens, radiation therapy or history of exposure to alkylating agent, that is secondary. In all cases of acute leukemia, only a small number of clinical MDS can be clearly observed in the process. About 50% MDS patients with specific chromosomal abnormalities can be seen. Way MDS patients and whether the progress of transformation to acute leukemia, depends largely on the cell type is activated and the number of cancer genes. The disease is currently considered to occur at an early stage hematopoietic stem cells after damage to the result of clonal variation. Of bone marrow cells and chromosome banding analysis of G6PD isoenzymes, suggesting that MDS system evolved from a stem cell, so for cloning disease. Clinical manifestations of the disease onset and more insidious, more common in middle-aged male, about 70% of cases 50 years of age. Rare in children, but also increased incidence of young people in recent years. Diverse clinical manifestations, the lack of specific performance, often to anemia, bleeding and infection treatment, some patients may be asymptomatic, was found in the examination process. 1, anemia: In addition to individual patients, the vast majority of patients with varying degrees of symptoms as the main clinical manifestations of anemia, such as pale, dizziness, fatigue, shortness of breath, palpitations, etc. after the event. 2, bleeding: more than half of the patients had bleeding, but the early symptoms of mild bleeding, mostly for skin and mucous membrane bleeding, gum bleeding or epistaxis, because not serious and rarely require special treatment, women are rarely seen in patients with menorrhagia ; But with the development of the disease to the late, increased bleeding tendency, as in patients with cerebral hemorrhage leading cause of death. 3, the infection: neutropenia and function due to abnormal result in infection, early disease (refractory anemia, RA) more stable, more non-serious infections and fever, the late (RAEB or RAEBt) easier to co-infection. As low immunity, easy to cause potential abscess and septic arthritis, tuberculosis, Pseudomonas aeruginosa conjunctivitis, gangrene and other unusual infections. Fungal infection in the latter part of the more common, often septic complications and end-stage disease, the major cause of death. 4, the signs: some patients the liver, spleen, lymph nodes may have mild swelling, which can occur, but also occur alone was not significant because of the degree was easily ignored. Small number of patients may have tenderness of sternum, ribs or limbs, joint pain. MDS, the lack of specificity of symptoms onset, some patients may be no obvious symptoms. Most patients have dizziness, fatigue, abdominal discomfort and bone and joint pain. Most of onset of anemia, can be used as the first symptom of treatment, continuing for several months to several years. About 20% to 60% of the cases with bleeding tendency in the course of the disease, degree of severity varies, the performance of skin petechiae. Gum bleeding, epistaxis. Severe cases may have gastrointestinal or cerebral hemorrhage. Reduce bleeding and platelet related, some patients have defects in platelet function. About half of the patients in the course of the disease are fever, fever and infection, heat-type variable, respiratory infections, while the rest had sepsis, perianal, perineal infection. Without conversion to acute leukemia cases, infection and / or bleeding is the main cause of death. Liver, spleen, or may have mild swelling, 1 / 3 of the patients had enlarged lymph nodes, as painless. Individual patients with sternal tenderness. A laboratory ex
Myelodysplastic syndrome therapy cells increased (RAEB), or changes in RAEB (RAEB-T) is often marked pancytopenia. Second, most patients bone marrow or bone marrow hyperplasia was extremely active, a small number of normal or reduced proliferation. MDS abnormal cell morphology reflects the pathological hematopoiesis. Immature erythroid cells in various stages of degeneration, often accompanied by class megaloblastic nuclear imbalance mature plasma, red blood cell volume large or oval, with basophilic stippling, nuclear fragmentation, and Howell-Jolly bodies. RA-S can be detected ring sideroblasts. Granulocyte in RAEB and RAEB-T were seen higher than normal proportion of primitive cells. Coarse grain granular cytoplasm or decrease in the nuclear sub leaves too much or too little, there Pelger-Hu