Myelodysplastic syndromes (MDS) are a group of heterogeneous myeloid clonal diseases originating from hematopoietic stem cells, characterized by abnormal development of myeloid cells, manifested by ineffective hematopoiesis, refractory hematocrit, and high risk of transformation to acute myeloid endohematopathy (AML). To further improve the diagnosis and treatment of MDS in China, the Hematology Branch of the Chinese Medical Association has reached the following consensus based on the Expert Consensus on the Diagnosis and Treatment of Myelodysplastic Syndromes (2012), which combines the latest clinical research results in the field of MDS and the actual situation in China in recent years.
I. Diagnosis
1. Diagnostic criteria: Two necessary conditions and one definitive criterion must be met for the diagnosis of MDS.
(1) Necessary conditions: (1) persistent hematocrit reduction in one or more lines: erythrocytes (HGB< 110g/L), neutrophils [absolute neutrophil count (ANC) <1.5x< span="">109/L], platelets (PLT< 100x109/L); (2) exclusion of other hematopoietic and non-hematopoietic system disorders that can lead to hematocrit reduction and abnormal development.
(2) Determination criteria: ① abnormal development: the proportion of abnormal cells in the erythroid cell lineage, granulocyte lineage and megakaryocyte lineage in the bone marrow smear is >10%; ② annular iron granulocytes occupy more than 15% of nuclear erythrocytes; ③ primitive cells: 5% to 19% in the bone marrow smear; ④ chromosomal abnormalities are common in MDS.
(3) Adjunctive criteria: (i) flow cytometry results showing abnormal bone marrow cell phenotype, suggesting the presence of monoclonal cell populations in the erythroid lineage and/or myeloid lineage; (ii) genetic analysis suggesting the presence of definite monoclonal cell populations; (iii) CFU (± cluster) formation of progenitor cells in bone marrow and/or peripheral blood is present and persistently reduced.
Testing for ancillary diagnostic criteria for MDS should be performed when the patient meets the necessary criteria, does not meet definitive criteria (atypical chromosomal abnormalities, developmental abnormal cells <10%, proportion of progenitor cells ≤4%, etc.), has common clinical manifestations of MDS such as transfusion-dependent macrocytic anemia, or has a clinical presentation that is highly suspicious of MDS. If the ancillary tests are not performed or the results are negative, the patient is followed up or temporarily classified as idiopathiccytopenia of undetermined significance (ICUS). Some ICUS may develop into typical MDS, so the patient should be closely monitored and diagnosed with MDS if typical cytogenetic abnormalities appear during follow-up, even if there is still a lack of primary cell increase and abnormal cell development,
The diagnosis of MDS is still to some extent an exclusionary diagnosis, and other factors or diseases that may lead to reactive cytopenia or abnormal cytogenesis should be excluded first. include.
① Vitamin B12 and folic acid deficiency.
② Receiving cytotoxic drugs, cytokine therapy or exposure to hematotoxic chemicals or biologics, etc.
③ chronic disease anemia (infection, non-infectious inflammation or tumor), chronic liver disease, HIV infection.
④ autoimmune hematocrit, hypothyroidism or other thyroid disorders.
⑤ heavy metal poisoning, excessive alcohol consumption.
⑥ Other diseases that can involve hematopoietic stem cells, such as aplastic anemia, primary myelofibrosis (especially to be identified e with MDS with fibrosis), large granular lymphocytic endolymphocytosis (LGL), paroxysmal sleep hemoglobinuria (PNH), acute leukemia [especially in patients with morphologic features of abnormal blood cell development or acute myeloid leukemia (AML)-M7] and other congenital or hereditary hematologic disorders (e.g., congenital abnormal erythropoietic anemia, hereditary iron granulocytic anemia, congenital dyskeratosis, Fanconi anemia, congenital neutropenia, and congenital pure red blood cell aplastic anemia).
3.Diagnostic methods of MDS: MDS diagnosis depends on the combined use of various laboratory testing techniques, among which bone marrow cytomorphology and cytogenetic testing techniques are the core of MDS diagnosis. the main diagnostic methods of MDS are shown in Table 1.
4, cell morphology testing: morphological abnormalities in peripheral blood and bone marrow of MDS patients are divided into two categories: increased proportion of primitive cells and abnormal cell development. The primitive cells can be divided into 2 types: type I are primitive cells without asplenophilic granules; type II are primitive cells containing asplenophilic granules but without paranuclear Golgi area, and those with paranuclear Golgi area are judged as early juvenile granulocytes. In a typical patient with MDS, the proportion of abnormal developmental cells in the corresponding cell series is ≥10%. All patients with proposed MDS should undergo bone marrow iron staining to count ringed iron granules in young erythrocytes, defined as those with more than 5 blue granules in the cytoplasm of young erythrocytes and more than 1/3 of the circumference around the nucleus.
All patients suspected of having MDS should undergo a bone marrow pathology biopsy, usually at the posterior superior iliac spine, of at least 1.5 cm in length. bone marrow pathology biopsy helps to exclude other factors or diseases that may contribute to hematocrit and provides important information about the degree of cellular proliferation, megakaryocyte count, primitive cell population, myelofibrosis, and tumor marrow metastasis. Gomori silver staining and in situ immunohistochemistry (immunohisto-chemical, IHC) are recommended for patients suspected of having MDS. Commonly tested markers include CD34, MPO, GPA, CD61, CD42, CD68, CD20 and CD3.
5. Cytogenetic testing: All patients with suspected MDS should undergo karyotype testing, which usually requires analysis of ≥20 mid-phase divisions of bone marrow cells and karyotype description according to the Inter-Synchronous System of Human Cytogenetic Nomenclature (ISCN) 2013. 40% to 60% of patients with MDS have non-random chromosomal abnormalities, with -5/5q-, – 7/7q-, + 8, 20q-, and -Y are the most frequent. some of the common chromosomal abnormalities in MDS patients have specific diagnostic value, including -7/7q-, -5/5q-, i(17q)/t (17p), -13/13q-, 11q-, 12p-/t (12p), 9q-, idic(X) (q13), t(11;16) (q23 p13.3), t(3; 21)(q26.2; q22.1), t(1; 3)(p36.3; q21.2), t(2; 11)(p21; q23), inv(3)(q21; q26.2), and t(6; 9)(p23; q34). Whereas +8, 20q- and -Y can also be seen in aplastic anemia and other non-clonal hemocytopenic disorders, some patients with +8, 20q- or -Y alone have effective immunosuppressive therapy and do not show morphologic basis suggestive of MDS at long-term follow-up. Patients whose morphology does not meet the criteria (<10% of abnormal cell development in one or more lines) but who also have persistent hemocytopenia should be diagnosed with mds unclassifiable (mds-u) if cytogenetic abnormalities of diagnostic value for mds are detected. < span="">
The application of FISH testing with sets of probes targeting common abnormalities in MDS may improve the detection rate of cytogenetic abnormalities in some MDS patients. Therefore, FISH testing can be performed in suspected MDS patients with bone marrow stem draws, no intermediate split phase, poor quality split phase, or <20 analyzable intermediate split phases, and usually probes should include: 5q31, cep7, 7q31, cep8, 20q, cepy, and p53.< span="">
6, Flow cytometry detection: No MDS-specific antigenic markers or combinations of markers have been identified, but flow cytometry has application for the differential e diagnosis of low-risk MDS and non-clonal hemocytopenia. For patients without typical morphology, cytogenetic evidence and unable to confirm the diagnosis of MDS, flow cytometry detection with ≥ 3 abnormal antigenic markers suggests the possibility of MDS.
7, Molecular genetic testing:Gene microarray technologies such as single nucleotide polymorphism microarray (SNP-array) can detect DNA copy number abnormalities and uniparental diploidy in most MDS patients, thus further improving the detection rate of cytogenetic abnormalities in MDS patients. In units where it is available, SNP-array can be a useful supplement to conventional karyotyping. With the widespread use of high-throughput technologies such as gene chips and second-generation gene sequencing, somatic mutations can be detected in most MDS patients, and common mutations include TET2, RUNX1, ASXL1, DNMT3A, EZH2, N-RAS/K-RAS, SF3B1, etc. The detection of common mutations has potential application for the diagnosis of MDS.
II. Typing recommendations
1. FAB typing: In 1982, the FAB Collaborative Group proposed a morphology-based MDS typing system (Table 2), which mainly classifies MDS into 5 types based on the characteristics of abnormal development of peripheral blood and bone marrow cells in MDS patients, especially e is the proportion of primitive cells, the proportion of ringed iron granulocytes, Auer vesicles and the number of peripheral blood mononuclear cells: refractory anemia ( refractoryanemia (RA), RAwith ringed sideroblasts (RAS), RA with excess blasts (RAEB), RAEBin transformation (RAEB-t), and chronic myelomonocytosis (CMP). The following are the categories of chronic myelomonocytic leukemia (CMML).
WHO (2008) typing: In 1997, WHO started to revise the FAB typing scheme for MDS, and in 2008, WHO introduced the revised MDS typing scheme (WHO 2008) (Table 3). Currently, WHO2008 typing has been widely accepted, and all patients with MDS should be diagnostically classified according to the WHO2008 typing scheme. Compared with the FAB typing, the main changes include the following: (1) the threshold of bone marrow primitive cell ratio for the diagnosis of AML was reduced from 30% to 20%, and the RAEB-1 subtype was incorporated into AML; (2) the subtype of refractory hematocrit with monophyletic developmental abnormalities (RCUD) was added; (3) CMML was classified into a new myeloid neoplasm category eMDS/myeloproliferative neoplasm (MPN); (4) one additional subtype with 5q- as the classification feature was added. (iv) adding one subclass with 5q- as a classification feature: MDS with simple 5q-; (v) classifying cyclic iron granulocytes with multilineage developmental abnormalities (RCMD-RS) into RCMD; (vi) classifying RAEB into RAEB-1 and RAEB-2 according to the proportion of primitive cells in peripheral blood and bone marrow.
III. Prognostic grouping
1. Inter-Parietal Post-Scale Scoring System (IPSS): IPSS is based on FAB typing and can assess the course of the patient’s disease toward the natural. The grading of risk is determined according to the following 3 factors: percentage of primitive cells, degree of hematocrit and cytogenetic characteristics of the bone marrow (Table 4).
2. Revised IPSS (IPSS-R): In 2012, the International Working Group on MDS Prognosis revised the IPSS prognostic scoring system based on the results of 5 MDS databases with a total of 7012 MDS patients, and refined grouping points for karyotype, bone marrow primordial cell count, and degree of hematocrit (Table 5). The karyotype analysis results are the most important parameters of the IPSS-R classification, which is divided into 5 levelse.
3. prognostic scoring system based on WHO classification (WPSS): erythrocyte transfusion dependence and iron overload not only lead to organ damage but also can directly impair hematopoietic system function, which may affect the natural course of MDS patients. the revised WPSS prognostic scoring system in 2011 changed the scoring basis from erythrocyte transfusion dependence to intrahemoglobin levels. the WPSS serves as a time-continuous evaluation system, the prognosis can be assessed at any stage of the patient’s course.
IV. Treatment
The natural course and prognosis of patients with MDS are highly variable and treatment should be individualized. MDS patients can be divided into two groups according to the prognostic grouping system: relatively low-risk group (IPSS-low risk, intermediate-risk-1 group, IPSS-R-very-low risk, low-risk and intermediate-risk group, WPSS-very-low risk, low-risk and intermediate-risk group) and relatively high-risk group (IPSS-medium risk). Patients in the IPSS-R-intermediate risk group will be treated in the relative low-risk group or relative high-risk group based on other prognostic factors such as age at onset, physical status, serum iron levels and LDH levels, and the low-risk regimen may be used for those with poor outcomes. The high-risk group may also be used if the low-risk regimen is not effective. The goal of treatment for patients with MDS in the low-risk group is to improve hematopoiesis and quality of life (Figure 1), while the goal of treatment for MDS in the high-risk group is to delay disease progression, prolong survival and cure.
1. Treatment: The most important goal of supporting the cure is to improve the quality of life of patients. This includes blood transfusion, EPO, G-CSF or GM-CSF and iron removal therapy.
(1) Component blood transfusion: Generally, red blood cell transfusion can be given when HGB<60g/L or accompanied by clear anemia symptoms. Platelet transfusion should be given when PLT<10x< span="">109/L or when there is active bleeding.
(2) Hematopoietic growth factors: G-CSF/GM-CSF is recommended for patients with MDS who are neutrophil deficient and have recurrent or persistent infections.
Transfusion-dependent patients in the relatively low-risk group of MDS patients can be treated with EPO±G-CSF. The response rate to epo therapy is higher in mds patients with pretreatment EPO levels <500 U/L and milder red blood cell transfusion dependence (<4u per month). < span="">
(3) Iron removal therapy: Iron overload can occur in patients receiving transfusion therapy, especially in those who are red blood cell transfusion dependent, and can lead to shorter survival in transfusion dependent MDS patients. In addition, iron overload can also lead to decreased survival in MDS patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). Therefore, patients with red blood cell transfusion-dependent MDS should be monitored regularly for serum iron SF levels, cumulative transfusion volume and organ function (heart, liver, pancreas) to evaluate the degree of iron overload. Iron removal therapy can be effective in reducing SF levels and iron content in organs. patients with MDS with SF >1000 μg/L can receive iron removal therapy. Commonly used iron removal drugs include desferrioxamine and deferasirox.
2. Immunomodulatory therapy: commonly used immunomodulatory drugs include thalidomide and lenalidomide. Some patients can improve erythropoietic hematopoiesis and reduce or get rid of transfusion dependence after receiving thalidomide treatment, however, patients often have difficulty in tolerating the adverse effects such as neurotoxicity after long-term application of thalidomide treatment. For patients with IPSS-low- or intermediate-risk group 1 MDS with 5q-, who have transfusion-dependent anemia and are not responding well to cytokine therapy, lenalidomide therapy can be used to reduce or eliminate transfusion dependence in some patients and achieve cytogenetic remission and prolonged survival. The usual dose of lenalidomide is 10 mg/dx21 d, with 28 d as a course of treatment. Lenalidomide is not recommended for patients with MDS with 5q- if the following conditions occur: bone marrow primitive cell percentage >5%; complex chromosomal abnormalities; IPSS-intermediate risk 2 or high risk group; detection of p53 gene mutation.
3. Demethylating drugs: commonly used demethylating drugs include 5-aza-2-deoxycytidine (decitabine, decitabine) and 5-aza-cytidine (azacitidine, AZA). Demethylating drugs can be used in the relatively high-risk group of MDS patients, and the group treated with demethylating drugs can reduce the risk of progression to AML and improve survival compared to the supportive care group. Patients with MDS in the relatively low-risk group who develop severe hematocrit and/or transfusion dependence may also be treated with demethylating drugs to improve hematocrit and reduce or wean them from transfusion dependence.
(1) Decitabine: The recommended dose is 20 mg?m-2?d-1x5d for a course of 28d. It is recommended that patients with MDS receive decitabine for 4-6 courses to evaluate treatment response, and effective patients can continue to use it.
(2) AZA: The recommended use is 75 mg?m-2?d-1x7d by subcutaneous injection or intravenous infusion for 28d as a course of treatment. The median time to first treatment response for MDS patients treated with AZA is 3 courses, and approximately 90% of patients with effective treatment achieve a treatment response within 6 courses. Therefore, it is recommended that MDS patients receiving AZA be evaluated for treatment response after 6 courses of therapy, and effective patients can continue to use it.
4, chemotherapy: relatively high-risk group, especially the prognosis of patients with increased proportion of primitive cells is poor, chemotherapy is one of its treatment modalities, but the standard AML induction regimen has a low rate of complete remission, short remission time, and is often difficult to tolerate in elderly patients, about 30%. Pre-excitation regimens are low-dose cytarabine (10 mg/m2 once every 12 h, subcutaneously, x14d) on top of G-CSF and combined with aclarubicin or hypertrigonelline or desoxorubicin. Pre-excitation regimen is widely used within the same for MDS patients in the relatively high-risk group, and the complete remission rate of treating MDS patients in the relatively high-risk group can reach 40%-60%, and the top-excitation regimen is better tolerated than conventional AML chemotherapy regimen in elderly or poorly functioning patients.
5.allo-HSCT: allo-HSCT is the only method that can cure MDS, and the sources of HSCT include sibling allogeneic donors, non-hematopoietic donors and haploidentical hematopoietic donors. indications for allo-HSCT: 1) patients aged <65 years with relatively high-risk group of MDS; 2) low-risk patients aged <65 years with severe hematocrit and ineffective with other treatments . Patients to be treated with allo-HSCT, such as bone marrow primitive cells > 5%, can apply chemotherapy or combined demethylating drugs to bridge allo-HSCT while waiting for transplantation, but the transplantation should not be delayed.
6. Immunosuppressive therapy (IST): IST, i.e., anti-thymocyte globule intravitreal monotherapy or combined with cyclosporine, may be considered in patients with the following conditions: low or intermediate-risk-1 IPSS ≤60 years of age, bone marrow primitive cell percentage <5% or hypoplasia, normal karyotype or simple +8, presence of transfusion dependency, hla-dr15, or presence of pnh clone. < span="">
V. Efficacy and follow-up
The International Working Group (IWG) on MDS proposed inter-agency uniform efficacy criteria in 2000 and further revised them in 2006 to make the results comparable between different clinical regimens. The treatment response for MDS includes four types: alteration of the natural course of the disease, cytogenetic response, hematologic improvement, and improvement in quality of life.