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 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, an International Consensus Working Group 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 specific molecular markers

Classification

In 2022, updates to internationally recognized MDS classifications were made. The WHO and International Consensus Consortium (ICC) both released guidelines with updated criteria for classification. 

The most recent WHO MDS classifications categorize MDS either by the defining cytogenetic or morphological characteristics of a patient’s dysplastic cells:²⁰

• MDS with defining genetic abnormalities:
  • MDS-5q (MDS with low blasts and isolated 5q deletion)
  • MDS-SF3B1 (MDS with low blasts and SF3B1 mutation)
  • MDS-biTP53) (MDS with biallelic TP53 inactivation) 
• MDS, morphologically defined:
  • MDS-LB (MDS with low blasts)
  • MDS-h (MDS, hypoplastic)
  • MDS-IB (MDS with increased blasts): includes MDS-IB1, MDS-IB2, and MDS-f (MDS with fibrosis)

In contrast, the ICC was created to provide an alternative classification system to the WHO system. Despite some overlap between WHO 2022 and ICC categories, the ICC system predominantly focuses on a patient’s number of dysplastic lineages and introduces a new category of MDS/AML:²¹

• MDS-SF3B1 (MDS with mutated SF3B1)
• MDS-del(5q) (MDS with del[5q])
• MDS, NOS without dysplasia (MDS, not otherwise specified [NOS] without dysplasia)
• MDS, NOS with single-lineage dysplasia
• MDS, NOS with multilineage dysplasia
• MDS-EB (MDS with excess blasts)
• MDS/AML (10-19% blasts present in bone marrow or peripheral blood)

NCCN Guidelines® for MDS have yet to adopt either WHO 2022 or ICC as the primary method of disease classification in MDS and continue to use the WHO 2016 system. These six categories rely mainly on the degree of dysplasia and blast percentages for disease classification:¹

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

Risk Assessment

Blast percentage may be used to distinguish MDS from AML and also separate 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):
  • Luspatercept for anemia in patients with ring sideroblastic lower-risk MDS
  • 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 transplant 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 prolonging overall survival while preventing cytopenia-related morbidity and preserving quality of life

There is a need to improve outcomes associated with azacitidine after more than 15 years of no further drug approvals in HR-MDS.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.