| 1- Summary of the disease |
Myelodysplastic syndrome ( MDS) comprises a very heterogeneous group of myeloid malignancies with very different natural histories. The prevalence increases with age and affects men more frequently than women. Exposure to previous chemotherapy or radiotherapy is a factor to consider. There is an increased risk of infections, bleeding and transformation to acute myeloid leukemia (AML).
Myelodysplastic syndrome (MDS) is usually suspected by the presence of cytopenia on a routine peripheral blood test.
This prompts evaluation of bone marrow cell morphology (aspirate) and cellularity (biopsy). A manual count of blasts in the bone marrow is essential for risk assessment.
Patients with MDS can be stratified according to several internationally accepted scoring systems. The original IPSS and the modified IPSS-R are the most widely used systems. These two systems are also important because they serve as part of the main eligibility criteria for past and ongoing registration clinical trials. Recently, molecular data have been incorporated to calculate prognosis in MDS, resulting in the new IPSS-M classification.
Several other important data points are needed when making therapeutic decisions. These include patient age, type and severity of comorbidity, significance and number of cytopenias, transfusion needs, presence of specific genomic alterations (now calculated by IPSS-M), percentage of blasts, cytogenetic profile, potential for transplantation. allogeneic stem cell (alloSCT) and, most importantly, pretreatment with a hypomethylating agent (HMA). This is critical as the biology and natural history of patients with MDS who have been treated with an HMA is very different from that of patients not previously treated with such an agent with similar IPSS and IPSS-R scoring systems.
| 2- Diagnosis |
The diagnosis of MDS is usually suspected based on the presence of cytopenia and confirmed by performing a bone marrow aspiration and biopsy . Both procedures provide different information.
- Bone marrow aspirate allows a detailed evaluation of cellular morphology and evaluation of the percentage of blasts.
- Bone marrow biopsy allows the cellularity and architecture of the bone marrow to be determined. The diagnosis is established by the presence of dysplasia .
Several morphological classifications have been established. The most recent is the 2022 WHO classification. Under this classification, MDS is now myelodysplastic neoplasia (MDS). The author of this work states that changing the name is a mistake since these disorders are clearly syndromic and not just neoplasms.
Several additional tests are needed to complete the laboratory evaluation of a patient with MDS. It is well established that cytogenetic patterns are very heterogeneous. Cytogenetics is of importance to estimate the prognosis of patients and, in some subgroups, to select the most effective form of therapy. The most recent cytogenetic risk classification in MDS includes 5 different subgroups that include 20 different alterations.
> 2.1 ICUS, clonal hematopoiesis of undetermined potential and CCUS
In general, the diagnosis is obvious in patients with excess blasts.
The problem is in patients without excess blasts where the diagnosis is based on dysplasia.
Clinical evaluation is necessary in patients with minimal or nondiagnostic evidence of dysplasia. In these cases, it is recommended to exclude other causes of cytopenia.
Routine tests include analysis for anemia and thrombocytopenia, and exclusion of the cause of blood loss or inflammatory processes. When suspected, evaluation of the gastrointestinal tract should be considered .
Once other possible causes of cytopenia are excluded, additional tools, including cytogenetic evaluation, flow cytometry, and more recently, DNA sequencing, can help define the diagnosis and predict patient outcomes.
Patients with cytopenia but no dysplasia are considered to have idiopathic cytopenia of undetermined significance (ICUS). The presence of a somatic mutation in the context of cytopenias without diagnostic criteria for MDS is now considered clonal cytopenia of undetermined significance (CCUS). This distinction is supported by data suggesting that although about 25% of ICUS patients may eventually develop MDS or AML, this risk increases significantly in the presence of a clonal mutation from 9% to 82% at 5 years, particularly in the presence of highly predictive mutation patterns. Therefore, a detailed evaluation and careful differential diagnosis between ICUS, CCUS, and MDS is essential ( table 1 ).
| Characteristics | CHIP | ICUS | CCUS | SMD |
| Cytopenia | No | Yeah | Yeah | Yeah |
| Dysplasia | No | None or minimal (non-diagnostic for MDS) | None or minimal (non-diagnostic for MDS) | Yeah |
| Somatic mutations | Yes at a variant allele frequency ≥2%. Mostly: DNMT3A, TET2, ASXL1 | No. ICUS defined by absence of clonality | Yes, like in CHIP | Yes. Up to 85% of patients |
| Risk of progression | Very low (0.5%–1% per year) outside of therapy-related setting. | Very low | Up to 80% at 5 years but determined by mutational patterns. | - |
Table 1. ICUS/CHIP/CCUS characteristics. Abbreviations: CCUS, clonal cytopenia of undetermined significance; CHIP, clonal hematopoiesis of indeterminate potential; ICUS, idiopathic cytopenia of undetermined significance; MDS, myelodysplastic syndromes.
| 3- Risk stratification |
The prognosis of patients with MDS is very heterogeneous and hence the need to develop systems that allow risk stratification and help in the timing and choice of therapy. The most commonly accepted system is the International Prognostic Scoring System-Revised (IPSS-R). Recently genomic data have been incorporated resulting in the new IPSS-M classification.
| 4- Cytogenetic and molecular alterations |
Over the last decade, several very important studies have been published describing a comprehensive analysis of the incidence and clinical impact of multiple genetic lesions in MDS.
Despite the heterogeneity of some of these studies, mutations in genes such as RUNX1, TP53 or EZH2 have been consistently associated with a poor prognosis, while mutations in the SF3B1 factor are associated with favorable outcomes and prolonged survival.
| 5- Risk-adapted therapy |
> 5.1 Current conceptual framework for MDS therapy in 2023
Patients were divided into six different categories. First is the subgroup of patients without a morphological diagnosis of MDS that includes ICUS, CHIP, and CCUS. MDS patients were then divided into lower or higher risk, but divided based on whether they have been exposed to an HMA: lower risk MDS, lower risk HMA failure, higher risk, and higher risk HMA failure. risk.
Finally, a group of patients with an extremely poor prognosis is AML patients who progress from MDS, particularly after HMA-based therapy. The author expresses that this last subgroup of patients will not be discussed in this review.
> 5.2 Treatment of ICUS/CHIP/CCUS
There are currently no data to support the treatment of patients with ICUS/CHIP/CCUS. People with ICUS have a very low risk of progressing to myeloid neoplasia (MN). These individuals could be followed on an outpatient basis. Patients with CHIP and CCUS present molecular alterations, and particularly in the context of cytopenia (CCUS), they should be followed up more frequently. Several institutions are developing “CHIP clinics” to follow these patients and develop care guidelines.
Another important finding associated with CHIP/CCUS is not only the increased risk of transformation to NM but also the collateral risk of associated comorbidities. Therapies targeting those comorbidities, i.e. cardiovascular diseases, are justified and should be monitored in clinical trials.
> 5.3 Options for lower-risk MDS patients
Therapy in this subgroup of patients is based on transfusion needs. In general, patients who are not transfusion dependent are usually observed until they become transfusion dependent. This concept is currently being questioned.
The use of erythrocyte stimulating agents (ESAs) is common practice.
A course of ESA with or without G-CSF is not contraindicated in most low-risk MDS patients with significant anemia without other cytopenia. The data indicate that early incorporation of these agents is more effective. Therapy is continued for at least 3 months to judge effectiveness. In patients who respond, it is continued until the effect of the transfusion is lost.
- Luspatercept : is the standard of care for patients dependent on red blood cell transfusions who have not responded, have lost response, or are not candidates for an ESA.
Lenalidomide is approved for patients with lower-risk MDS, anemia, and chromosome 5 alteration. The degree of response with lenalidomide in patients with lower-risk MDS, anemia, good platelet count, and MDS-5q makes it the standard of care for this subgroup of patients. This is reinforced by data on survival in responding patients. The author does not consider this agent in patients with thrombocytopenia.
Based on the results of a randomized phase III study, lenalidomide may be considered an option for selected RBC transfusion-dependent patients without MDS-5q. Assessment of TP53 mutation status might be advisable in patients with MDS-5q before starting lenalidomide therapy. Although current evidence does not support discontinuation of lenalidomide treatment in patients with TP53 mutations, these patients should be closely monitored for signs of inadequate response, loss of response, or progression.
- Azanucleosides : three azanucleosides are approved for MDS: 5-azacytidine and 5-aza-2’-deoxycytidine (decitabine) and in 2020 decitabine/cedazuridine oral (dac/ced oral, ASTX727).
Both 5-azacytidine and decitabine are used in the US in patients with lower-risk disease who are transfusion-dependent. Most patients treated with these agents failed or were not candidates for ASA or
lenalidomide. Although results from randomized studies will be needed to determine whether these agents can modify the natural history of low-risk disease and be considered standard of care in the first-line setting or after ASA, recent data support the use of these agents in higher doses
low, particularly in patients with more adverse characteristics.
- Immune therapy : this is an area of controversy. It is accepted that a subgroup of patients with MDS is characterized by a dysregulation of both cellular and innate immunity. Based on this, it will be logical that the use of immunomodulatory agents could have a therapeutic benefit in MDS. The NIH group pioneered this approach. Agents studied include antithymocyte globulin (ATG), cyclosporine, steroids.
Alemtuzumab, an antibody against CD52, has been reported to have significant activity in patients with MDS who are expected to respond to immunosuppressive therapy. However, the most important response predictor for the authors of the present work has been the presence of marrow hypocellularity.
- Allogeneic stem cell transplantation : alloSCT is generally not recommended in patients with lower risk disease at initial presentation. That said, due to the time required for donor identification, all potential candidate patients are referred for a transplant consultation in anticipation of future needs.
Patients who are candidates for alloSCT and have been exposed to multiple therapies (growth factors, lenalidomide, azanucleosides, etc.) should be considered for transplant. These patients are also candidates for clinical trials. Those with hypoplastic MDS who are young should be considered for alloSCT early on.
- Supportive measures in MDS : the authors do not routinely recommend antibiotics in patients with isolated neutropenia and MDS who do not receive some type of cytotoxic or immunosuppressive therapy. They use prophylactic antibiotics in patients receiving active therapy. Iron chelation is indicated in patients with ferritin levels greater than 2500 ng/ml, but all of these patients are considered for a clinical trial of iron chelation.
- Thrombomimetic agents: should be used with caution and probably only in refractory patients with no other options.
> 5.4 Options for patients with relapsed or refractory low-risk MDS and new investigational agents in low-risk MDS
There is currently no approved drug for low-risk MDS patients with HMA failure. The only active option is alloSCT. Otherwise, patients should be considered for a clinical research trial.
> 5.5 Options for patients newly diagnosed with high-risk MDS
Options for patients with higher-risk MDS have not evolved significantly since the last version of this document. Azanucleosides remain the standard of care for most patients.
No studies have compared 5-azacytidine versus decitabine. Although response rates appear to be similar, only 5-azacytidine has been associated with improved survival in a randomized trial. Based on this, standard therapy with 5-azacytidine is considered as first-line treatment in high-risk MDS.
- AML-like chemotherapy : The AZA-001 randomized study was not designed to demonstrate superiority of 5-azacytidine versus LMA-like therapy. The reason for this is that most researchers did not consider their patients candidates for such therapy. Therefore, the question is who can be a candidate for AML therapy.
In practice, this is restricted to younger patients with a high probability of response to therapy, such as diploid patients or candidates for alloSCT. AML therapy was rarely used in older patients or those with low-risk cytogenetics or TP53 mutation.
- AlloSCT: All potential candidate patients for alloSCT should be counseled about the possibilities of undergoing alloSCT. Optimally, patients will be enrolled in an MDS-specific clinical trial of alloSCT. Although alloSCT should be considered for patients with higher-risk MDS, this may not be the case in those with high-risk mutations such as TP53, in whom, in the author’s opinion, transplantation should be considered only if an optimal donor is available. optimal response prior to transplant. has been obtained and whether lower doses of 5-azacytidine or decitabine are considered post-transplant. Lower doses of 5-azacytidine may also be administered.
> 5.6 Research approaches for patients with higher MDS
The results of the AZA-001 trial still represent the best standard of care for patients with higher-risk disease. In that study, patients with higher-risk MDS were randomized to receive azacitidine or the investigator’s choice of treatment. Overall survival (24 months) was significantly higher than that of the control.
Although the median survival of patients with high-risk MDS is disputed at 24 months and probably shorter, these results still represent the best data from a randomized trial in this setting and, therefore, single-agent azacitidine constitutes the objective for improvement.
> 5.7 HMA failure remains a major unmet need in MDS
The prognosis of patients with HMA failure is very poor. The natural history differs between patients who are still in a lower risk category, where survival is 15 to 17 months, versus those with higher risk failure who have a survival of 4 to 6 months.
Currently, there is no therapy that has been shown to have significant activity for this group of patients. For patients at higher risk of HMA failure, options that have been investigated included rigosertib, venetoclax, guadecitabine, among several.
> 5.8 Incorporation of precision medicine in SMD
One of the major advances in MDS research has been the incorporation of NGS assays, first in the laboratory and now in the clinic. These data not only allow for a better understanding and prognosis of the disease, but also the design of specific approaches for patients with MDS.
Genes of interest include SF3B1, IDH2, IDH1, Flt-3, p53, and the small subset of patients with NPM1-mutated disease. SF3B1 is involved in gene splicing and is the most commonly mutated gene in MDS.
| 6- Conclusions |
A better understanding of the pathophysiology of MDS is resulting in newer approaches for patients. As a result, the treatment landscape is beginning to change.
Luspatercept was the first agent approved for MDS since 2006. This was followed in 2020 by the oral HMA decitabine/oral cedazuridine (ASTX727). In 2023, results are expected from the initial trial of luspatercept in low-risk MDS (COMMANDS, NCT03682536) and of imetelstat in second line (iMERGE NCT02598661).
Additionally, 2 large phase 3 trials have been completed for higher risk diseases (Verona and Enhance). Results with alloSCT continue to improve. All of these efforts should result in improved survival of patients with MDS.
