What are the key prognostic factors for Myelodysplastic Syndromes (MDS)?

MDS Prognostic Factors

All patients with MDS must be risk-stratified using the International Prognostic Scoring System (IPSS), which incorporates bone marrow blast percentage, cytogenetic abnormalities, and number of cytopenias as the three critical prognostic factors. 1

Core Disease-Related Prognostic Factors

The IPSS remains the reference standard for clinical decision-making and clinical trial design, despite newer scoring systems offering refinements. 1 The three fundamental components are:

Bone Marrow Blast Percentage

• Higher blast percentages predict worse survival and increased risk of AML transformation 1
• Patients with 5-9% blasts have significantly worse outcomes compared to those with <5% blasts, even within lower-risk cytogenetic categories 2
• The IPSS-R provides refined blast categories for enhanced prognostic precision 1

Cytogenetic Abnormalities

• Cytogenetics represent the most powerful prognostic indicator in MDS 3, 2
• The IPSS-R expanded cytogenetic stratification into 5 risk groups based on a large multicenter dataset, allowing prognostic assessment of even rare karyotypic abnormalities 1
• Poor-risk cytogenetics (complex karyotype, chromosome 7 abnormalities) are associated with median survival less than 5 years 4
• Favorable cytogenetics (isolated del(5q), normal karyotype, -Y) predict better outcomes 4

Peripheral Blood Cytopenias

• The number and severity of cytopenias independently predict survival 1
• Severity of cytopenias (not just presence) significantly influences outcome in multivariate analysis 2
• The IPSS-R includes refined categories for peripheral blood cytopenias beyond the original IPSS 1

Additional Disease-Related Factors

Multilineage Dysplasia and Transfusion Dependency

• Multilineage dysplasia, severe anemia/transfusion dependency, and bone marrow fibrosis add prognostic value beyond IPSS 1
• These factors are incorporated into the WHO Classification-Based Prognostic Scoring System (WPSS), which stratifies patients into 5 risk groups 1
• The WPSS provides more accurate prognostic definition particularly for patients in IPSS low or intermediate-1 risk groups 1
• Transfusion dependency is an independent adverse prognostic factor 2

Somatic Mutations

• Mutations in TET2, SF3B1, ASXL1, SRSF2, RUNX1, DNMT3A, U2AF1, TP53, and IDH1/2 influence overall survival and disease progression 1, 4
• Somatic mutations are detected in 52-78% of MDS patients when combined with cytogenetics 1
• Integration of somatic mutations into prognostic scoring may provide more accurate risk stratification, though routine clinical use is not yet recommended 1, 4

Flow Cytometry

• Multiple flow cytometric abnormalities combined into numerical scores provide additive prognostic value to reference scoring systems 1
• Flow cytometry can identify patient subsets with distinct clinical courses and treatment responses, though routine use is not recommended 1

Patient-Related Prognostic Factors

Age

• Increasing age is an independent adverse prognostic factor for survival 1, 4
• Age-adjusted survival estimates are incorporated into various prognostic scoring systems 4

Performance Status and Comorbidities

• ECOG performance status independently predicts survival 1, 4
• Cardiovascular comorbidities significantly impact overall survival 4
• These patient-related variables are incorporated into comprehensive risk models that include both disease and patient characteristics 1

Recommended Prognostic Scoring Systems

Primary Recommendation: IPSS

All patients must be stratified using IPSS because current therapeutic evidence and regulatory drug approvals are based on IPSS risk categories. 1, 4

Supplementary Systems

• IPSS-R: Provides enhanced prognostic precision with 5 risk groups and should be used in prospective registries and clinical studies 1, 4
• WPSS: Adds value particularly for lower-risk patients by incorporating WHO classification, transfusion dependency, and bone marrow fibrosis 1, 4

Clinical Application Algorithm

1. At diagnosis, calculate IPSS score using bone marrow blasts, cytogenetics, and cytopenias 1
2. Stratify into risk categories: Low, Intermediate-1 (lower-risk) versus Intermediate-2, High (higher-risk) 1, 4
3. For lower-risk patients (IPSS Low/Int-1), additionally assess WPSS to identify those with worse prognosis based on transfusion dependency and multilineage dysplasia 1
4. Calculate IPSS-R for more refined prognostic information, particularly useful for clinical trial enrollment 1
5. Consider patient factors including age, performance status, and comorbidities when determining treatment approach 1, 4

Common Pitfalls

• Do not rely solely on FAB classification for prognostic assessment, as significant outcome heterogeneity exists within morphologic subtypes 1
• Avoid using only blast percentage without incorporating cytogenetics and cytopenias, as this misses critical prognostic information 3
• Recognize that lower-risk disease by IPSS is heterogeneous: patients with 5-9% blasts, severe cytopenias, or transfusion dependency within this category have significantly worse outcomes 2
• Remember that IPSS was developed for untreated patients: prognostic factors may differ in patients receiving hypomethylating agents or other disease-modifying therapies 4