Myelodysplastic syndromes (MDS) are a heterogeneous group of myeloid clonal disorders of hematopoietic stem cell origin, characterized by ineffective hematopoiesis, resulting in a reduction of blood cells in the blood, which can transform into acute myeloid leukemia in one third of patients. 15% of patients with MDS develop it secondary to radiotherapy for other primary tumors, a condition more common in the elderly The pathophysiological mechanisms of MDS The pathophysiological mechanism of MDS involves cytogenetic alterations (with or without genetic mutations) and extensive methylation of genes may occur in advanced patients.
The prognosis of MDS is largely determined by the percentage of primitive cells in the bone marrow, the degree of blood cell decline and the presence of cytogenetic abnormalities. The prognosis of MDS depends largely on the percentage of primitive cells in the bone marrow, the degree of blood cell decline and the presence of cytogenetic abnormalities.
Treatment of low-risk MDS, especially in patients with anemia, consists of growth factors, lenalidomide, and blood transfusions. Demethylating drugs and allogeneic hematopoietic stem cell transplantation may be considered in high-risk patients.
Morbidity and etiology
The average age of patients diagnosed with MDS is 65 to 70 years, and approximately 10% of patients are under 50 years of age. The annual incidence of MDS is approximately 4 per 100,000 and no racial differences have been found. Compared to Western countries, Asian patients have an earlier age of onset and fewer patients with 5q deficiency.
Approximately 15% of patients with MDS have a definite cause. Approximately one-third of pediatric patients have a genetic predisposition. These genetic disorders include Down syndrome, Fanconi anemia, and neurofibromas. In adults, genetic causes of MDS are uncommon, but a history should be taken to ask if there are similar patients in the family, such as MDS, acute myeloid leukemia, or aplastic anemia.
Environmental factors contributing to MDS include previous chemotherapy, especially alkylating agents and purine analogs, radiation therapy, and smoking. Long-term exposure to benzene and benzene analogs is an occupational susceptible group. A higher incidence of MDS has also been reported in farmers and workers, which may be related to long-term exposure to fertilizers, pesticides, stone, rubber, plastic, and glass wire. Patients with MDS secondary to chemotherapy tend to have a poor prognosis because their cytogenetics become extraordinarily complex.
Causes of MDS
Antineoplastic agents
Alkylating agents
leucovorin
Carboplatin
Carmustine
Azelaic acid benzoate
Cisplatin
Cyclophosphamide
Dacarbazine
Lomustine
Marfalan
Topoisomerase II inhibitors
Zoloftin
Doxorubicin
Etoposide
Mitoxantrone
Razoxan
Purine analogues
Fludarabine and its derivatives
Radiotherapy
Environmental factors
Smoking
Ionizing radiation
Exposure to benzene and industrial hydrocarbons
Agricultural compounds (pesticides, herbicides, fertilizers)
Diagnosis
The clinical presentation of MDS is often atypical, and many patients have symptoms of thrombocytopenia, mainly in the form of malaise, decreased quality of life, and potential cardiovascular accidents. Thrombocytopenia is usually associated with abnormal platelet function, and even moderate thrombocytopenia can lead to bleeding. Similarly, moderate thrombocytopenia can lead to infections (especially gram-negative bacilli, gram-positive cocci, and fungi) due to functional defects in the patient’s neutrophils. Most patients with MDS have concomitant immune system disorders, including recurrent polychondritis, vasculitis, and seronegative arthritis; the two disorders often occur together, implying that there may be some pathophysiologic relationship.
Peripheral blood and bone marrow tests
Ninety percent of patients with MDS have anemia, with the majority presenting as macrocytic aplastic anemia. One-third of MDS patients have neutropenia and thrombocytopenia, and some patients, but no more than 5%, have primitive cells in the peripheral blood. However, in order to properly type MDS, 200 cells should be counted on a blood smear; the typing of MDS depends in part on the percentage of primitive cells in the peripheral blood.
Bone marrow smears are the primary method of diagnosing MDS; the bone marrow picture of MDS usually has an increase in primitive cells with pathological hematopoiesis of one or several myeloid blood cells; the bone marrow picture of MDS is different from that of vitamin B12 and folic acid deficiency. A minimum of 500 nucleated cells should be counted for primitive bone marrow cells (including non-granulocytes and progranulocytes). Ringed iron granulocytes should be counted after Prussian blue staining.
Usually, a bone marrow aspiration biopsy is sufficient to diagnose MDS; however, 15% of patients with MDS may present with myelofibrosis, and a bone marrow ring drill biopsy is better for diagnosing MDS with myelofibrosis and hypoplasia, differentiating it from aplastic anemia and acute myelogenous leukemia. In cases where the proportion of primitive cells is low, bone marrow ring drill biopsy can detect abnormal localization of immature precursor cells, which often predicts a poorer prognosis for the patient.
Differential diagnosis
The main clinical manifestation of MDS is a decrease in blood cells, in addition to other factors that need to be ruled out as causes of hematocrit. Other conditions that can cause hematocrit include vitamin deficiencies, autoimmune diseases, liver disease, hypersplenism, pharmacologic factors, exposure to toxic substances, aplastic anemia, paroxysmal sleep hemoglobinuria, bone marrow infiltration by malignancy, viral infections, and rare genetic anemias. The diagnosis is often more difficult if the hematocrit is moderate and the bone marrow dysplasia is mild. If the patient has chromosomal abnormalities in the bone marrow cells, it can be classified as an early myelodysplastic syndrome. If not, the diagnosis is idiopathic thrombocytopenia.
Cytogenetic analysis
Karyotype testing should be performed in all patients with suspected MDS. 20 to 25 mid-phase divisions of myeloid cells need to be detected. Most acute myeloid leukemias are characterized by chromosomal translocations, whereas MDS is often characterized by partial or complete chromosomal deletions. -5/5q-, -7/7q-, +8, -20/20q-, etc. are the most common of the karyotype types of chromosomal abnormalities. Patients with primitive cells in the bone marrow or treated MDS tend to have more complex karyotypes (two or more karyotypic abnormalities), and FISH combined with conventional cytogenetic testing can increase the detection rate of chromosomal abnormalities.
Cytogenetic analysis is valuable in determining the prognosis of MDS, and also has diagnostic value in difficult cases. These cases include unexplained platelet separation (20q-), mild anemia in older patients (5q-), and moderate hematocrit in younger patients (-7q or +8q). Several of these cases demonstrate the clonal nature of MDS.
Typing
The World Health Organization introduced a new classification of MDS in 2008, based more on the study of genetics. The latest classifications include: refractory anemia with an increase in bone marrow primitive cells, refractory anemia with or without ringed iron granulocytes, refractory hemocytopenia with multilineage dysplasia, and myelodysplastic syndrome with 5q-. Among these, treatment-related MDS is classified separately, and treatment-related acute myeloid leukemia is also included in this classification.
Prognostic factors
IPSS Prognostic Scoring System
The IPSS is the most commonly used system to assess the prognosis of MDS in clinical practice. it calculates the score as a group of patients who have not been previously treated, which allows assessing the natural course of the disease. the IPSS indicates that the prognosis of MDS correlates with the degree of hematocrit, primitive cell count, chromosomes, and age. Current treatment of MDS is mostly based on IPSS prognostic groupings. This prognostic score system is proposed to help standardize MDS treatment studies, allow comparison of data from different published studies, and make recommendations for the selection of allogeneic hematopoietic stem cell transplantation (Allo-HSCT) and other treatments for patients with MDS.
The IPSS scoring system also has shortcomings. It is based on the FAB diagnostic staging, summarized by the initial presentation of new primary MDS patients, and excludes the application of the IPSS at various time points during the later stages of disease progression. the IPSS also excludes patients with CMML and secondary MDS. As a result, experts have modified the IPSS scoring system (IPSS-R).
Other factors
Age is an important factor in the prognosis of MDS, but is not included in the IPSS score because advanced age is often combined with other diseases, and comorbidities may be a real factor in prognosis, which need to be considered in subsequent treatment. In addition, myelofibrosis is an independent risk factor for the prognosis of MDS.
MDS prognosis is greatly influenced by patient characteristics such as age and comorbidities. the IPSS is valuable, but not yet precise. the WPSS and MDACC approaches offer new options. continued research on the molecular pathogenesis of MDS and biological predictors of drug efficacy will provide new insights into MDS prognosis.
Treatment
The treatment of MDS has improved significantly in recent years, but remains challenging. The choice of treatment is primarily based on the patient’s IPSS score; patients with an IPSS score of high or intermediate risk -2 (high risk) have a median survival of only about 12 months without treatment. The primary goal of treatment for these patients is to control disease progression, prolong patient survival, and avoid progression to AML. In contrast, patients with an IPSS score of low or intermediate risk 1 (low risk) have a longer survival and often die from a combination of other complications rather than from MDS per se. Therefore, the main goal of their treatment is to improve anemia and improve the patient’s quality of life. However, studies have shown that some low-risk patients may also benefit from treatment.
Allogeneic Hematopoietic Stem Cell Transplantation
Allogeneic HSCT is currently the only effective treatment for high-risk MDS, resulting in long-term disease-free survival in 35-50% of patients, but it is only available for some younger patients. Patients older than 70 years of age who are in good general condition may receive reduced intensity stem cell transplantation.
The majority of patients with MDS have comorbidities or other organ impairments that lead to poor outcomes. Allogeneic hematopoietic stem cell transplantation carries the following risks: 1) mortality associated with transplantation in patients hoping for long survival; and 2) risk of relapse after transplantation in patients with advanced disease. The need for transplantation, and the optimal timing of transplantation, must balance both of these risks. In high-risk patients, whether they are <60< span=""> years of age, receive a clear-cut pretreatment transplant, or older patients receive a non-clear-cut transplant, early HSCT can benefit such patients compared with other treatment options. In contrast, low-risk patients do not benefit from HSCT.
Chemotherapy
Prior to HSCT, patients with a high percentage of primitive cells in the bone marrow are at high risk of relapse. Therefore, cytoreduction (chemotherapy or demethylating drugs) should be performed prior to stem cell transplantation in patients with a high percentage of primitive cells in the bone marrow. However, to date, there are no prospective findings to support this treatment approach. The more potent chemotherapy regimen is a combination including anthracyclines and cytarabine, which results in complete remission in approximately 40-60% of patients. This regimen is also currently the chemotherapy regimen for acute myeloid leukemia. The complete remission rate and duration of remission are shorter for patients with a poor prognosis abnormal karyotype.
Non-drug combinations (including single-agent fludarabine, topotecan, gituzumab, and cytarabine, with or without G-CSF regimens) prolong patient survival compared with the classic anthracycline plus cytarabine combination. Therefore, a stronger regimen of chemotherapy is usually chosen for younger <65< span=""> year-old patients with MDS with no cytogenetic abnormalities and at high risk for preparation for allogeneic hematopoietic stem cell transplantation. Low-dose cytarabine (20 mg/m2 per day for 14–21 days) may achieve partial or complete remission in 15–20% of high-risk patients, but does not improve patient survival. This regimen is also effective only in some patients without abnormal karyotypes.
Demethylating drugs
These drugs are now the first-line treatment option for high-risk MDS patients, and demethylating drugs currently include decitabine and azacitidine. Clinical studies have shown clear efficacy of azacitidine in patients with MDS, with low doses of azacitidine prolonging survival and significantly delaying the transformation of MDS to acute myeloid leukemia compared to conventional treatment regimens, including supportive care.
Azacitidine can benefit patients regardless of their age, the percentage of primitive cells in the bone marrow, or the presence of karyotypic abnormalities. Current guidelines recommend that azacitidine not be discontinued until disease progression, or unacceptable toxic side effects occur, but the optimal timing of dosing is unclear. Results from 2 recent clinical studies suggest that decitabine + supportive therapy has similar efficacy to azacitidine alone; adjuvant supportive therapy failed to improve patient survival.
Patients with high-risk MDS treated with azacitidine have a median survival of only 2 years; therefore, the combination of other agents is necessary. Azacitidine in combination with valproic acid, vorinostat, entinostat, lenalidomide, thalidomide, and gituzumab may improve the response rate to treatment. However, to date, no clinical studies have shown that these drug combinations improve patient survival.
Demethylating drugs are now increasingly used as induction therapy prior to HSCT in patients with a high proportion of primitive cells in the bone marrow or abnormal karyotype, with the aim of reducing the risk of relapse after transplantation and reducing the toxic side effects after chemotherapy.