(i) 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). The current treatment of MDS is mostly based on IPSS prognostic grouping. Liu Lingbo, Department of Hematology, Wuhan Union Medical College Hospital
Table 5 International Prognostic Score System (IPSS) for myelodysplastic syndromes
Prognostic variables
Criteria
Integral
Bone marrow primitive cells
<5%
5% to 10%
11%～20%
21%～30%
0
0.5
1.5
2.0
Chromosome karyotype
Good [normal, -Y, del(5q), del(20q)
Moderate (remaining abnormalities)
Poor [complex (3 abnormalities) or abnormal chromosome 7
0
0.5
1.0
Hematocrita
None or reduced in one lineage
Two or three lineage decreases
0
0.5
Note: a Neutrophil count <1.5×109/L, HGB <100g/L, PLT <100×109/L
Evaluation: The IPSS scoring system divides MDS patients into two subgroups: low-risk group (low and intermediate-risk-1) and 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 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.
Because the criteria for blood transfusion are not easily standardized and hemoglobin levels were found to have a significant impact on prognosis in men <90∥L and women <80/L. Therefore, a new revision of the WPSS was made in 2011 (Table 6), and its subgroup scores remained unchanged.
Table 6 Myelodysplastic syndrome (MDS) WHO staging prognostic score system (WPSS, 2011)
Prognostic variables
Criteria
Score
WHO staging
RCUD, RARS, MDS with simple 5q-
RCMD
RAEB-1
RAEB-2
0
1.0
2.0
3.0
Chromosome karyotype
Good [normal, -Y, del(5q), del(20q)
Moderate (actually normal)
Poor [complex (≥3 abnormalities) or abnormal chromosome 7
0
1.0
2.0
Anemia
Male HGB <90g/L, female HGB <80g/L
None
Yes
0
1.0
Evaluation: WPSS, as a time-continuous evaluation system, allows the prognosis to be assessed at any stage of the patient’s disease.
(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, immunomodulators, and epigenetic drugs. 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 poor prognosis, are prone to transformation 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 appropriate 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 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, 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 may be tried even if blood EPO levels are elevated, and the addition of G-CSF may 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 orally once daily for 3 weeks with 1 week off, or 5mg orally once daily 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 the MDS clone. 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 doses, which re-express the already silenced epigenetic oncogenes, induce further differentiation and apoptosis of malignant clones and inhibit proliferation, also increase the immunogenicity of tumor cells by inducing the expression of multiple immune-related molecules in malignant clonal cells, and induce the killing of tumors by immune cells in vivo; cytotoxic effect at high doses. Oncogene methylation is frequently seen 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-aza-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 in a 4-week course. Most patients start at the end of the second course and achieve optimal results at the same time point. The full dose of decitabine is usually applied 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 therapy.
Application considerations: ① myelosuppression should not be taken lightly; ② the first treatment response is mostly obtained in the first 2 courses of treatment, and the median time to start to show effect is about 2 months; ③ the duration of treatment is decided according to the treatment response, and some patients need to be postponed; ④ predictive index: the overall response rate is not high with a long course of demethylation treatment, and the treatment cost is high for domestic patients, so it is very important to find effective indicators that can predict the efficacy. Therefore, it is important to find effective indicators to predict the efficacy of the treatment; no target gene has been found to predict the efficacy of the treatment as a demethylation indicator.
(6) Allogeneic hematopoietic stem cell transplantation has no evidence-based basis for early and 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 is more efficacious than bone marrow transplantation.
2. Treatment of intermediate to 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 transfusion. desferrioxamine can be discontinued when SF falls below 500 μg/L and the patient no longer requires transfusion, 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. On the premise that toxicity is tolerated and peripheral blood count indicates no progression, those who do not improve after 6 courses of AZA treatment are switched to other drugs.
DAC 20mg/m2/d×5d, every 4 weeks; adjust the dosage according to the patient’s condition.
There are no reports that AZA and DAC can cure MDS, but because of their cumulative effect on MDS clones, maintenance therapy is relatively necessary.
Because of their cumulative effect on MDS clones, maintenance therapy is relatively necessary.
② Chemotherapy.
The prognosis is relatively poor for patients with MDS in the high-risk group, especially those with the primitive cellular 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 for these patients to prolong survival and improve quality of life. The complete remission rate for the treatment of MDS is 40% to 60%, and the effective 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%-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. The prognosis of patients with MDS who have not achieved CR is poor, and HSCT is used as salvage therapy for these patients, and disease recurrence or non-relapse death is still the main reason for treatment failure in these patients without CR, and even if CR is achieved after HSCT, the CR period is short, and demethylation therapy needs to be used to maintain treatment and prolong overall survival and event-free survival; some studies suggest that the application of AZA before HSCT reduces the rate of relapse within one year and does not affect transplantation therapy. Some studies suggest that the application of AZA before HSCT can reduce the recurrence rate within one year and does not affect the transplantation efficacy. The main reason for transplant failure in high-risk patients is relapse.
In conclusion, 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.