In-hospital management of patients with thrombocytopenia caused by hematological diseases (4) - myelodysplastic syndrome

Author: LIU Jia Jun, Third Affiliated Hospital of Sun Yat-sen Hematology article is the author's permission NMT Medical publish, please do not reprint without authorization
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Myelodysplastic syndromes (MDS) are a group of heterogeneous myeloid clonal diseases originating from hematopoietic stem cells, characterized by abnormal development of myeloid cells, manifested as ineffective hematopoiesis, refractory cytopenia, and high risk of acute myeloid development.
leukemia (AML) transformation
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MDS can present with thrombocytopenia and is one of the diagnoses to be considered in patients with thrombocytopenia
.

MDS assessment and process diagnostic criteria The minimum diagnostic criteria for MDS are shown in Table 1
.

The criteria for cytopenia were: absolute neutrophil value <1.
8 × 109 /L, hemoglobin <100 g/L, and platelet count <100 × 109 /L
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The diagnosis of MDS is established by the exclusion of precursor diseases that may develop into MDS, including idiopathic cytopenia of undetermined significance (ICUS), clonal hematopoiesis of undetermined potential (CHIP), and clonal cytopenias of undetermined significance (CCUS)
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The typical characteristics of ICUS, CHIP, CCUS and MDS are compared in Table 2
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Diagnostic methods The diagnosis of MDS relies on the comprehensive use of a variety of laboratory detection techniques, among which the cytomorphological and cytogenetic detection techniques of bone marrow aspirate smear are the core of the diagnosis of MDS (Table 3)
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(1) Detection of cell morphology: The morphological abnormalities in peripheral blood and bone marrow smears of MDS patients are divided into two categories: increased proportion of blast cells and abnormal cell development
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The blasts can be divided into two types: type I is the blast without azurophilic granules; type II is blasts with azurophilic granules but no paranuclear halo area.
promyelocytes
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In typical MDS patients, dysplastic cells account for ≥10% of the corresponding lineage cells
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All patients with suspected MDS should undergo bone marrow iron staining to count ring-shaped sideroblasts, which are defined as those with more than 5 blue granules in the cytoplasm of the erythrocytes and more than 1/3 surrounding the nucleus
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All patients with suspected MDS should undergo a bone marrow biopsy, usually at the posterior superior iliac spine, at least 1.
5 cm in length
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Patients suspected of MDS should undergo Gomori silver staining and in situ immunohistochemistry (IHC).
Commonly used markers include CD34, MPO, GPA, CD61, CD42, CD68, CD20, and CD3
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(2) Cytogenetic testing: All patients with suspected MDS should undergo karyotype testing, usually requiring analysis of metaphase images of ≥20 bone marrow cells
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40% to 60% of MDS patients have nonrandom chromosomal abnormalities, among which +8, -7/del(7q), del(20q), -5/del(5q) and -Y are the most common
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Patients whose morphology does not meet the standard (the proportion of dysplasia of one or more lineages <10%) but are accompanied by persistent cytopenias should be diagnosed as undifferentiated MDS if cytogenetic abnormalities with diagnostic value for MDS are detected.
Type (MDS-U)
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Fluorescence in situ hybridization (FISH) was used to detect common abnormalities in MDS by using a set of probes to improve the detection rate of cytogenetic abnormalities in some MDS patients
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Therefore, for suspected MDS patients, if bone marrow aspirate, no metaphase, poor quality of mitoses or less than 20 analyzable metaphases, FISH detection should be performed, usually the probes should include: 5q31, CEP7, 7q31, CEP8, 20q, CEPY and TP53
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(3) Flow cytometry (FCM): There is currently no MDS-specific antigen marker or marker combination
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However, FCM has application value for the prognostic stratification of MDS and the differential diagnosis of low-risk MDS and nonclonal cytopenias
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For patients without typical morphological and cytogenetic evidence and unable to diagnose MDS, FCM test results can be used as one of the auxiliary diagnostic criteria
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(4) Molecular genetic testing: Next-generation gene sequencing technology can detect at least one gene mutation in the vast majority of MDS patients
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Common gene mutations in MDS include TET2, RUNX1, ASXL1, DNMT3A, EZH2, SF3B1,
etc.

Common gene mutation detection has potential application value in the diagnosis of MDS.
For example, SF3B1 gene mutation has important diagnostic and differential diagnosis value for MDS with ring sideroblasts (MDS-RS) subtype, and should be a must-check gene
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The mutation status of some genes has a certain value in the differential diagnosis and risk stratification of MDS, and is recommended as an optional test item, including: TP53, TET2, DNMT3A, IDH1/2, EZH2, ASXL1, SRSF2, RUNX1, U2AF1, SETBP1 et al
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In addition, the presence of gene mutation does not mean that the diagnosis of MDS can be established, and the value of gene mutation in the diagnosis of MDS should be carefully judged in combination with other indicators
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Gene chip technologies such as single nucleotide polymorphism-microarray comparative genomic hybridization (SNP-array) can detect DNA copy number abnormalities and uniparental diploidy in most MDS patients, further improving the risk of cytogenetic abnormalities in MDS patients.
The detection rate, in conditional units, can be used as a useful supplement to routine karyotyping
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Disease classification (1) FAB classification (Table 4) (2) WHO classification (Table 5) Risk stratification (1) IPSS score: Table 6 (2) WPSS score: Table 7 (3) IPSS-R score : Table 8 Treatment and supportive care of MDS (1) Component blood transfusion: Generally, red blood cell transfusion can be given when HGB is less than 60 g/L or accompanied by obvious symptoms of anemia
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When the patient is elderly, the body's compensatory ability is limited, and the oxygen demand is increased, it is recommended to give red blood cell transfusion when the HGB is less than or equal to 80 g/L
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Platelet transfusion should be given when PLT is less than 10×109/L or there is active bleeding
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(2) Hematopoietic growth factor: G-CSF/GM-CSF, recommended for MDS patients with neutropenia and recurrent or persistent infections
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Transfusion-dependent lower-risk MDS patients can be treated with EPO±G-CSF.
EPO treatment response rate is higher in MDS patients with pre-treatment EPO level <500 IU/ml and less red blood cell transfusion dependence (<8 U per month)
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(3) Iron removal therapy: For patients who are dependent on red blood cell transfusion, serum ferritin (SF) level, cumulative blood transfusion volume and organ function monitoring (heart, liver, pancreas) should be regularly monitored to evaluate the degree of iron overload
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Iron removal therapy can effectively reduce SF levels and iron content in organs
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For patients with life expectancy ≥ 1 year, total amount of more than 80 U, SF ≥ 1000 μg/L for at least 2 months, and transfusion-dependent patients, iron removal therapy can be implemented, and SF is the main monitoring and control index (the goal is to control SF at 500～1000 μg/L)
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Commonly used iron-removing drugs include deferoxamine and deferasirox
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Immunomodulatory drugs commonly used in the treatment of this disease include thalidomide and lenalidomide
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For lower-risk MDS patients with del(5q)±1 other abnormality (except -7/7q-), if there is transfusion-dependent anemia, lenalidomide treatment can be applied, and some patients can be relieved or eliminated Transfusion-dependent and obtain cytogenetic remission and prolong survival
.

For lower-risk MDS patients without del(5q), if they have transfusion-dependent anemia and are ineffective or unsuitable for cytokine therapy, lenalidomide therapy can also be selected
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The usual dose of lenalidomide is 10 mg/d × 21 d, and every 28 d is a course of treatment
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In MDS patients with del(5q), lenalidomide is not recommended if the following conditions occur: ① the proportion of bone marrow blasts > 5%; ② complex karyotype; ③ IPSS-intermediate-risk-2 or high-risk group; ④ TP53 gene mutation
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Adverse reactions such as neurotoxicity may occur with long-term use
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2 Immunosuppressive therapy Immunosuppressive therapy (IST), including antithymocyte globulin (ATG) and cyclosporine A, can be considered for patients with the following conditions: the prognosis is grouped as low risk, the proportion of bone marrow blasts is <5% Or myeloproliferative hypoplasia, normal karyotype or simple +8, transfusion-dependent, HLA-DR15 positive, or PNH clone
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3 Demethylation treatments include 5-azacitidine (AZA) and 5-aza-2-deoxycytidine (decitabine, decitabine)
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Applied to higher-risk MDS patients, it can reduce the risk of progression to AML and improve survival
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Lower-risk MDS patients with severe neutropenia and/or thrombocytopenia can also be treated with demethylating drugs to improve cytopenias
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AZA: The recommended usage is 75 mg·m-2·d-1 ×7 d, subcutaneous injection, and 28 d is a course of treatment.
It is recommended that MDS patients receive AZA treatment for 6 courses to evaluate the treatment response, and the effective patients can continue to use it
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Decitabine: One of the recommended regimens is 20 mg·m-2·d-1 ×5 d, with a course of treatment every 4 weeks
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It is recommended that MDS patients receive decitabine for 4 to 6 courses to evaluate the treatment response, and the effective patients can continue to use it
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4 The higher risk group of chemotherapy, especially the patients with increased blast cell ratio, have a poor prognosis.
Chemotherapy is one of the treatment methods for patients with non-hematopoietic stem cell transplantation (HSCT)
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AML standard 3+7 induction regimen or pre-excitation regimen can be adopted
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The pre-excitation regimen is widely used in high-risk MDS patients in China.
It is a low-dose cytarabine (10 mg/m2, once every 12 h, subcutaneous injection, × 14 d) plus G-CSF, combined with Accra or homoharringtonine or daunorubicin
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The complete remission rate of pre-excitation regimen in the treatment of high-risk MDS patients can reach 40% to 60%, and the tolerance of pre-excitation regimen is better than conventional AML chemotherapy regimen in elderly or patients with poor physical function
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Pre-excitation regimens can also be combined with demethylating drugs
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5allo-HSCT is currently the only method that can radically cure MDS.
The sources of hematopoietic stem cells include sibling homogenous donors, unrelated donors and haploidentical blood donors
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The indications of allo-HSCT are: ① age < 65 years old, high-risk group MDS patients; ② age < 65 years old, with severe cytopenia, ineffective after other treatments or with genetic abnormalities with poor prognosis (such as -7, 3q26 Rearrangement, TP53 gene mutation, complex karyotype, monosomal karyotype) in the lower-risk group
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For patients who are planning to undergo allo-HSCT, such as bone marrow blasts ≥ 5%, chemotherapy or demethylation drugs or a combination of both can be used to bridge allo-HSCT while waiting for transplantation, but transplantation should not be delayed
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6 Other androgens can promote erythropoiesis in some MDS patients with anemia, and are commonly used adjuvant drugs for MDS treatment, including danazol, stanozolol and testosterone undecanoate
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Liver function tests should be performed regularly in patients receiving androgen therapy
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In addition, it has been reported that all-trans retinoic acid and some traditional Chinese medicine ingredients have therapeutic effects on MDS, and further clinical trials are recommended to confirm
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Reference consensus: Chinese Guidelines for Diagnosis and Treatment of Myelodysplastic Syndrome (2019 Edition) RECOMMEND Recommended reading 1.
In-hospital management of patients with thrombocytopenia caused by blood system diseases (1) - immune thrombocytopenia 2.
Hematological diseases In-hospital management of patients with thrombocytopenia caused by blood system diseases (2) - aplastic anemia 3.
In-hospital management of patients with thrombocytopenia caused by blood system diseases (3) - hematopoietic stem cell transplantation