MDS are characterized by abnormal bone marrow and blood cell morphology and peripheral blood cytopenias.²

• A hallmark characteristic of MDS is ineffective hematopoiesis.
• As a result, there may be aberrant proliferation, differentiation, and apoptosis of the stem cell progenitors that are responsible for developing into mature blood cells.
• The clinical profile of the disease may include irregular numbers of blood cells, including:
  • High numbers of immature cells or "blasts" in peripheral blood or bone marrow and/or
  • Malformed red blood cells, platelets, and/or white blood cells—a condition commonly known as morphologic cell dysplasia
    • The signs and symptoms of the disease could manifest as anemia, thrombocytopenia, and/or leucopenia, respectively.

MDS is thought to originate in a hematopoietic stem cell and to be associated with the accrual of multiple genetic and epigenetic aberrations.⁹ MDS is further associated with genomic instability and a high propensity to progress into AML.

• Genomic instability is a condition in which cells are prone to acquire and accumulate permanent genomic alterations. Examples in MDS patients include:
  • The presence of increased numbers of micronuclei in lymphocytes compared to age-matched healthy individuals
  • The presence of microsatellite instability (MSI) in patients with therapy-related MDS/AML (t-MDS/AML)
  • 74%–90% of MDS patients have mutations in one of ~50 known cancer genes

Genomic instability is directly associated with an inability to cope with damaged DNA, either because of deficient response/repair mechanisms or because of too much DNA damage.⁹

Although MDS and AML have very similar clinical symptoms, they can be distinguished from each other by cell counts in the peripheral blood and pathological review of the bone marrow. Transformation of MDS into AML is defined by a boundary of ≥20% bone marrow blasts but does not necessarily reflect a defined biological transition.¹¹

Management of MDS relies on diagnosis, classification, risk assessment, and treatment.⁶

Diagnosis

The initial evaluation requires careful assessment of a peripheral blood smear and blood counts, bone marrow morphology, cytogenetics, duration of abnormal blood counts, other potential causes of cytopenias, and concomitant illnesses.¹

• To assist in providing consistency in the diagnostic guidelines from MDS, the international working group (IWG) recommended minimal diagnostic criteria for MDS include two prerequisites:
  • Stable cytopenia (for at least 6 months or 2 months if accompanied by a specific karyotype or bilineage dysplasia)
  • Exclusion of other potential disorders as a primary reason for dysplasia or cytopenia or both

In addition, the diagnosis of MDS requires at least one of three MDS-related (decisive) criteria:

1. dysplasia (≥10% in ≥1 of the 3 bone marrow [BM] lineages)
2. a blast cell count of 5%-19%
3. a specific MDS-associated karyotype

• Several co-criteria may help confirm the diagnosis of MDS, including:
  • Aberrant immunophenotype by flow cytometry
  • Abnormal BM histology and immunohistochemistry (IHC)
  • Presence of molecular markers

Classification

The six WHO MDS classifications rely mainly on the degree of dysplasia and blast percentages for disease classification and specific cytopenias have only minor impact on MDS:¹

1. MDS-SLD (MDS with single lineage dysplasia)
2. MDS-RS (MDS with ring sideroblasts)
3. MDS-MLD (MDS with multilineage dysplasia)
4. MDS-EB (MDS with excess blasts)
5. MDS with isolated del(5q) ± one other abnormality except -7/del(7q)
6. MDS-U (unclassifiable MDS)

Risk Assessment

Blast percentage not only distinguishes MDS from AML but it further represents a clear separator of MDS into Lower- and Higher-Risk subgroups.^1,8,9

• International Prognostic Scoring System (IPSS) for MDS uses relative risk scores for each significant variable (marrow blast percentages, cytogenetic subgroup, and number of cytopenias)
• The original IPSS was refined (IPSS-R) by incorporating more detailed cytogenetic subgroups, separate subgroups within the "marrow blasts <5%" group, and a depth of cytopenias measured defined with cutoffs for hemoglobin levels, platelet counts, and neutrophil counts
  • Patients are therefore classified into five risk groups:
    • very low
    • low
    • intermediate
    • high
    • very high
• IPSS-M improves the risk stratification of IPSS-R by combining genomic profiling with hematologic and cytogenetic parameters. There are 31 genes of interest in the calculation of IPSS-M (16 main effect genes and 15 residual ones). It classifies patients into six risk groups: very low, low, medium low, medium high, high, and very high. Compared with the IPSS-R, the IPSS-M results in improved prognostic accuracy cross all long-term clinical end points (OS, LFS, AML transformation) and restratified nearly half of patients with MDS (46%).¹⁸

Prognosis by Genetics

Several gene mutations have been identified among MDS patients that may, in part, contribute to the clinical heterogeneity of the disease course, and thereby influence prognosis of patients.¹²  In a study evaluating nearly 3000 patients, at least one oncogenic genomic alteration was identified in 94% of patients with MDS. Multivariable analysis identified TP53^multihit, FLT3 mutations, and MLL^PTD as top genetic predictors of adverse outcomes. Conversely, SF3B1 mutations were associated with favorable outcomes, but this was modulated by patterns of comutation. The outcomes of this study were used to develop the IPSS-M which incorporates somatic mutations of 31 genes into risk classification.¹⁸

The assessment of individual risk enables the identification of fit patients with a poor prognosis who are candidates for up-front intensive treatments, primarily allogeneic stem cell transplantation (allo-SCT).^1,14,15

The major therapeutic aim for patients in the lower risk group is hematologic improvement, whereas for those in the higher risk group, alteration of the natural history of disease is paramount.¹

• Lower-risk patients are typically treated with supportive care and low-intensity therapies (availability dependent on geography):
  • Transfusions for severe anemia and thrombocytopenia
  • Antimicrobial agents for suspected infections
  • Erythropoiesis-stimulating agent (ESAs) if the serum erythropoietin (sEPO) level is <500 U/L
  • Lenalidomide if del5q.
• Altering the natural history of disease for higher risk MDS patients is challenging and current treatment options are (availability dependent on geography):
  • Hypomethylating agents (HMAs)
  • High-intensity chemo
  • Allo-SCT
  • Clinical trials

A high proportion of MDS patients are not eligible for potentially curative treatment because of advanced age and/or clinically relevant comorbidities and poor performance status.^1,14,15

• In these patients, the therapeutic intervention is aimed at preventing cytopenia-related morbidity and preserving quality of life

Current therapeutic strategies such as azacitidine have an only short response duration in higher-risk MDS patients.⁸

Pro-apoptotic drug treatment may reduce the disease burden in higher-risk MDS patients by selectively killing leukemic progenitors as well as blast cells without significantly affecting the healthy progenitor cell population.⁸

• BH3-mimetic compounds might therefore represent an interesting approach to treat higher-risk MDS patients to delay progression into AML or to perform a bridging therapy for patients awaiting allo-SCT.