(A) Prognostic grouping
1. International Prognostic Scoring System (IPSS): IPSS is based on FAB typing and allows assessment of the natural course of the patient’s disease. The grading of risk is determined based on the following 3 factors: percentage of primitive cells, number of lineages with hematocrit and cytogenetic characteristics of the bone marrow. The groups are as follows: low risk (Low) 0 points; intermediate-risk-l (Int-1) 0.5 to 1.0 points; intermediate-risk-2 (Int-2) 1.5 to 2.0 points; high risk (High) ≥ 2.5 points (Table 5). Current treatment of MDS is mostly based on IPSS prognostic grouping.
EVALUATION: The IPSS scoring system divides MDS patients into two subgroups, the low-risk group (low and intermediate-risk-1) and the high-risk group (intermediate-risk-2 and high-risk). Its advantage is that the score is calculated for a group of patients who have not been previously treated and can assess the natural course of the disease. Disadvantage: it is based on the FAB diagnostic typing, summarized by the initial presentation of patients with new-onset primary MDS, and cannot be applied at various time points during the later development of the disease.
2. Prognostic scoring system (WPSS) based on WHO classification: Red blood cell transfusion dependence and iron overload not only lead to organ damage, but also can directly impair the function of the hematopoietic system, which may affect the natural course of MDS patients. This has led to the formation of the WPSS, including WHO typing, IPSS cytogenetic grouping, and red blood cell transfusion dependence. The subgroups are as follows: very low risk group (0 points), low risk group (1 point), intermediate risk group (2 points), high risk group (3-4 points), and very high risk group (5?6 points.) The WPSS serves as a time-continuous evaluation system that can be used to assess prognosis at any stage of a patient’s life.
(ii) Treatment
MDS treatment addresses two major issues: bone marrow failure and complications, and AML transformation. As far as the patient population is concerned, the natural course and prognosis of MDS patients vary greatly, and individualization of treatment is advisable. Treatment options are selected based on the prognostic score of MDS patients, along with a comprehensive assessment of the patient’s age, physical status, and adherence. Treatment for patients with MDS in the low-risk group includes component blood transfusion, hematopoietic factor therapy, immunomodulatory agents, and epigenetic drug therapy.
Chemotherapy and hematopoietic stem cell transplantation are generally not recommended for patients in the low-risk group, but patients in the younger low-risk group can tolerate high-intensity therapy, which is expected to produce better outcome/risk ratios and progression-free and overall survival rates. Patients in the high-risk group with MDS have a poorer prognosis, are prone to conversion to AML, and require high-intensity therapy, including chemotherapy and HSCT. High-intensity therapy has a high rate of treatment-related complications and morbidity and mortality and is not suitable for all patients.
1. Treatment of lower-risk MDS
Refers to patients with low-risk/intermediate-risk-1 by IPSS score ≤1.0, and MDS patients in the very low-risk, low-risk and intermediate-risk groups based on the WHO WPSS score ≤2.0.
(1) Treatment principles.
(1) Peripheral blood can maintain the following levels without active clinical treatment, as long as regular observation and herbal regulation are required. HGB 70-80g/L or above, PLT 20-30×109/L or above, and neutrophils around 1.0×109/L.
(2) Peripheral blood cells below these levels require blood product transfusion, and formal treatment is required only when there is fever and infection due to granulocytopenia.
(2) Supportive treatment mainly includes component blood transfusion and anti-infection.
Platelet transfusion: The recommended transfusion point for those with risk factors for platelet depletion [infection, bleeding, use of antibiotics or anti-human thymocyte globulin (ATG), etc.] is PLT 20×109 /L, while the transfusion point for those with stable disease is PLT 10×109 g/L.
In patients with neutrophil deficiency, G-CSF and/or GM-CSF may be given to achieve neutrophils >1.0×109/L. Routine antibiotic prophylaxis for infection in patients with MDS is not recommended.
Erythropoietic therapy: EPO is the main initial therapy for low-risk MDS, transfusion-dependent patients, 10,000 U/d × 3 months, and can also be combined with G-CSF. EPO can be tried even if blood EPO levels are elevated, and the addition of G-CSF can increase the erythropoietic response for up to 6 weeks. In non-responders, EPO can be added and treatment can continue for 6 weeks. For those who respond to treatment, once maximum efficacy is achieved, the dose of C-CSF and EPO will be gradually reduced until the original efficacy is maintained with the smallest dose.
Irradiated or depleted leukocytes and cytomegalovirus-negative blood products should be used for patients scheduled for allogeneic HSCT.
(3) Immunomodulatory therapy: Commonly used immunomodulatory drugs include thalidomide (thalidomide) and lenalidomide (1enalidomide).
Hematologic improvement after thalidomide treatment of patients is predominantly in the red lineage with long-lasting efficacy, but improvement in neutrophils and platelets is rare. A relationship between dose and response rate has not been demonstrated, and long-term application is poorly tolerated.
Lenalidomide is effective in chromosome 5q-abnormalities, but the standard dose (lenalidomide l0 m g/ d for 21 d) has a high rate of myelosuppression and therefore should not be used when neutropenia and thrombocytopenia are present. In individuals with complex chromosomal abnormalities and with p53 mutations, the use of lenalidomide can lead to disease progression. It is recommended that patients with 5q-syndrome start with EPO and switch to lenalidomide after failure. Testing for chromosomal and p53 mutations before and during lenalidomide administration.
Mechanism of action: Immunomodulation (enhancement of immunosurveillance function of cytotoxic T cells) and reduction of tumor tissue angiogenesis. It is mainly indicated for patients with anemia as the main manifestation, especially in combination with 5q-.
Dosage and major adverse effects: Lenalidomide 10mg once daily orally with 3 weeks stopping for 1 week, or 5mg once daily orally continuously. Major adverse reactions: bone marrow suppression and deep vein thrombosis. Thalidomide 100-200mg,qn; major adverse effects: drowsiness, constipation and deep vein thrombosis.
(4) Immunosuppressive therapy Principle: TCL and Th1 cell polarization, as well as mono- or oligoclonal T-cell Vβ receptors, can be detected in most low- to intermediate-risk patients, suggesting the presence of a T-cell immune response against MDS clones. If the response is too intense, excessive T cell-mediated apoptosis can involve residual hematopoietic cells and bone marrow failure can occur. Therefore, excessive T-cell immunity should be moderately controlled. Target: Bone marrow biopsy with <30% hyperplasia, positive HLA-DR15 allele, T-cell hyperimmunity; Contraindications: bone marrow primitive cells ≥5%; poor IPSS karyotype abnormalities, combined with non-hematologic tumors. Methods: CsA 3-5 mg.kg-1.d-1, ATG/ALG available for severe myelosuppression, followed by CsA.
(5) Epigenetic modification therapy (demethylation therapy)
Principle: Both drugs have demethylation effect at low dose, which makes the already silenced epigenetic oncogenes re-expressed, induces further differentiation and apoptosis of malignant clones and inhibits proliferation, also increases the immunogenicity of tumor cells by inducing the expression of various immune-related molecules in malignant clonal cells, and induces the killing of tumors by immune cells in vivo; cytotoxic effect at high dose. Oncogene methylation is frequent in patients with MDS.
Indications: Low-risk patients with concurrent severe hematocrit and/or transfusion dependency.
Contraindications: patients with MDS with extremely low myeloproliferation.
METHODS: The specific dosing regimen of 5-azacitidine (AZA) and 5-azacytidine 2-deoxycytidine (Decitabine, DAC) in the treatment of MDS is still being optimized.
DAC: The recommended regimen is 20 mg?m2?d-1 intravenous infusion for 3 to 5 d over a 4-week period. Most patients start at the end of the second course of treatment and achieve optimal results at the same time point. Decitabine is usually applied in adequate doses for 3 to 4 courses without effect before considering discontinuation of treatment. An overall response rate of about 25% can be achieved. Increasing the duration of therapy may improve the efficiency of AZA or decitabine treatment.
Application precautions:
①Myelosuppression should not be taken lightly;
②The first treatment response is usually obtained in the first 2 courses of treatment, and the median time to start to show effect is about 2 months;
③The duration of treatment should be decided according to the treatment response, and some patients need to postpone the drug;
(4) Predictive index: The overall response rate of demethylation treatment is not high due to the long duration of treatment and the high cost of treatment for domestic patients, so it is important to find effective indexes that can predict the efficacy of treatment; target genes that can predict the efficacy of treatment have not been found as demethylation indexes.
(6) Allogeneic hematopoietic stem cell transplantation lacks evidence-based medical basis for early unconditional selection of low-risk patients for transplantation. However, allogeneic HSCT should be decisively chosen for patients who cannot be removed from blood product transfusion dependence after various treatments and who may die from bone marrow failure. Because this type of MDS has different biological and clinical features than patients progressing to leukemia, pretreatment options should more closely resemble aplastic anemia than acute leukemia. Transplant failure in low-risk patients is mainly due to transplant-related comorbidities. Peripheral stem cell transplantation has better efficacy than bone marrow transplantation.
2. Treatment of medium- and high-risk MDS
Refers to patients with intermediate-risk-2/high-risk by IPSS score ≥ 1.5, and high-risk and very high-risk MDS by WHO-based WPSS score ≥ 3.0.
(1) Supportive treatment
①Blood transfusion
② Iron removal therapy Repeated blood transfusions can lead to iron overload and cause liver and heart dysfunction. Iron overload in patients receiving transfusion therapy, especially in red blood cell transfusion-dependent MDS, can lead to shorter overall survival if untreated or improperly treated.
Serum ferritin (SF) measurement can indirectly reflect the body’s iron load, but SF levels fluctuate widely and are susceptible to infection, inflammation, tumors, liver disease, and alcohol abuse. For patients dependent on red blood cell infusion, SF should be monitored 3 to 4 times a year. patients receiving iron removal therapy should have their iron load monitored according to the guidelines for the use of the selected drug, and the function of the involved organs should be evaluated regularly. Desferrioxamine can reduce SF levels and iron levels in the liver and heart, and its efficacy depends on the duration of drug administration, dose, patient tolerance, and concurrent transfusions. desferrioxamine can be discontinued when SF falls below 500 μg/L and the patient no longer requires transfusions, or if desferrioxamine is no longer the patient’s point of maximum benefit. Commonly used drugs include desferrioxamine, deferiprone, and deferasirox.
(iii) Antibiotic therapy Prophylactic application of antibiotics is not routinely used, but prophylactic application of antifungal drugs plays a role in the induction therapy of classical acute myeloid leukemia. In neutrophil-deficient patients with moderate-to-high-risk MDS combined with severe infections, granulocyte transfusions can be administered along with powerful antibiotics.
(4) Hematopoietic growth factor Application of EPO in combination with G-CSF for MDS reduces or eliminates transfusion and does not increase the risk of progression to AML.
(2) Removal of malignant clones of MDS
(1) Demethylation therapy: Currently available drugs are 5-azacytidine (AZA) and 5-azacytidine-2-deoxycytidine (Decitabine, DAC).
AZA: AZA 75 mg/m2 was administered to high-risk patients with MDS. 7 d of subcutaneous or intravenous infusion for 28 d is the currently recommended regimen. aZA significantly improved patients’ quality of life, reduced transfusion requirements, and significantly delayed conversion to AML or death in high-risk MDS patients. AZA improves survival even when patients do not achieve complete remission. DAC 20mg/m2/d×5d, every 4 weeks; dosage adjusted according to patient’s condition. There are no reports that AZA and DAC can cure MDS, but maintenance therapy is relatively necessary because of their cumulative effect on MDS clones.
② Chemotherapy.
The prognosis is relatively poor for patients with MDS in the high-risk group, especially in the primitive cell hyperplasia subtype, and it is advisable to start treatment similar to AML, with a complete remission rate of 40% to 60%, but the remission time is short. Patients of advanced age are often difficult to tolerate. The 5-year overall survival rate after chemotherapy is approximately 27% in patients <65 years of age with normal karyotype.
Pre-excitation regimens are low-dose cytarabine (Ara-C) (10 mg/ m2 every 12 h for ×14 d) plus G-CSF in combination with aclarubicin (ACR) or hypertrigonelline (HHT) or desoxorubicin (IDA). Pre-excitation regimens are mostly used in China. Since MDS is mostly seen in the elderly population with poor organismal status or often associated with factors such as chronic lung disease, cardiovascular disease and diabetes mellitus that are not suitable for strong chemotherapy, low-dose chemotherapy provides a treatment option to prolong survival and improve quality of life in these patients. The complete remission rate for the treatment of MDS is 40% to 60%, and the efficiency rate is 60% to 70%. Age has no significant effect on efficacy, but patients aged >60 years tolerate chemotherapy less well.
(iii) Hematopoietic stem cell transplantation (HSCT): MDS patients undergoing allogeneic transplantation have a long-term disease-free survival rate of only 30% to 40%, with the same or even higher transplant-related mortality, and survivors remain at long-term risk of chronic graft-versus-owner disease or other serious adverse effects.
Patients in CR before HSCT can improve disease-free survival and reduce the relapse rate with HSCT, whereas patients with MDS who do not achieve CR have a poor prognosis, and HSCT is used as salvage therapy for these patients, and disease relapse or non-relapse death remains the main reason for treatment failure in these non-CR patients, and even if CR is achieved after HSCT, the CR period is short, and elective demethylation therapy is required to maintain treatment. Prolonging overall survival and event-free survival; some studies suggest that the application of AZA before HSCT can reduce the relapse rate within one year and does not affect transplantation efficacy. The main reason for transplant failure in high-risk patients is recurrence.
In summary, despite the above mentioned treatments for MDS, there are no drugs available to cure the disease, and with the in-depth study of molecular mechanisms, it is believed that more and better targeted therapeutic drugs will be available.