The WHO classification-based Prognostic Scoring System (WPSS) represents a significant advancement in the prognostic assessment of myelodysplastic syndromes (MDS). Developed to address the limitations of earlier static scoring systems, WPSS offers a dynamic approach that can be applied at any point during a patient's disease course. This flexibility makes it particularly valuable for clinicians managing MDS patients, as it allows for ongoing risk reassessment as clinical conditions evolve.

Myelodysplastic syndromes are a heterogeneous group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis, peripheral cytopenias, and an increased risk of progression to acute myeloid leukemia (AML). The clinical course of MDS varies widely, with some patients experiencing indolent disease over many years while others progress rapidly to AML. This heterogeneity underscores the critical importance of accurate prognostic tools that can guide treatment decisions and patient counseling.

Historical Context and Development

The WPSS was developed in response to the need for a more refined prognostic system that could better capture the complexity of MDS. Prior to WPSS, the International Prognostic Scoring System (IPSS) was the gold standard, but it had limitations. The IPSS was a static system that could only be applied at diagnosis, and it did not incorporate the WHO classification system that had been updated to better reflect the biological diversity of MDS subtypes.

The development of WPSS was driven by several key observations. First, the WHO classification system provided more detailed categorization of MDS subtypes, which appeared to have prognostic significance. Second, cytogenetic abnormalities had been shown to be powerful predictors of outcome in MDS. Third, transfusion dependency emerged as an important clinical factor that reflected both disease severity and patient quality of life. By combining these three elements, researchers created a scoring system that could be applied dynamically throughout the disease course.

Components of the WPSS

WHO Classification

The first component of WPSS is the WHO classification of MDS subtypes. The World Health Organization classification system for MDS provides a detailed categorization based on morphological and cytogenetic features. In the WPSS, different WHO subtypes are assigned different point values:

• Refractory Anemia (RA), Refractory Anemia with Ringed Sideroblasts (RARS), and MDS with isolated del(5q): These subtypes are assigned 0 points, reflecting their generally more favorable prognosis. RA and RARS are characterized by unilineage dysplasia, typically affecting only the erythroid lineage, with RARS specifically showing ringed sideroblasts. The isolated del(5q) subtype has a unique biology and typically responds well to lenalidomide therapy.
• Refractory Cytopenia with Multilineage Dysplasia (RCMD) and RCMD with Ringed Sideroblasts (RCMD-RS): These subtypes receive 1 point. RCMD is characterized by dysplasia affecting two or more myeloid cell lines, indicating more extensive bone marrow involvement. The presence of ringed sideroblasts in RCMD-RS adds morphological complexity but does not significantly alter the prognostic score in this system.
• Refractory Anemia with Excess Blasts-1 (RAEB-1): This subtype receives 2 points. RAEB-1 is defined by having 5-9% blasts in the bone marrow, indicating progression toward a more aggressive disease state. The presence of excess blasts is a critical prognostic factor, as it suggests the disease is moving closer to transformation to AML.
• Refractory Anemia with Excess Blasts-2 (RAEB-2): This subtype receives 3 points, the highest score for WHO classification. RAEB-2 is characterized by 10-19% blasts in the bone marrow, representing a more advanced stage of disease with a significantly higher risk of progression to AML.

Cytogenetic Risk Categories

The second component of WPSS is cytogenetic risk assessment. Chromosomal abnormalities are among the most powerful prognostic factors in MDS, and the WPSS incorporates this through a three-tier classification system:

• Good Risk (0 points): This category includes normal karyotype, isolated -Y, isolated del(5q), and isolated del(20q). These cytogenetic findings are associated with a more favorable prognosis. The isolated del(5q) abnormality, in particular, has a unique biology and is often associated with a relatively indolent clinical course, especially when it occurs in isolation.
• Intermediate Risk (1 point): This category encompasses all cytogenetic abnormalities that do not fall into the "good" or "poor" categories. This includes various single and double abnormalities that have intermediate prognostic significance. The heterogeneity within this category reflects the complexity of cytogenetic abnormalities in MDS.
• Poor Risk (2 points): This category includes complex karyotypes (defined as three or more abnormalities) and chromosome 7 anomalies. These findings are associated with a poor prognosis and high risk of progression to AML. Complex karyotypes, in particular, are associated with aggressive disease and limited response to conventional therapies.

The cytogenetic risk assessment requires comprehensive karyotypic analysis, typically performed on bone marrow samples. The accuracy of this component depends on the quality of the cytogenetic analysis and the expertise of the cytogenetic laboratory. In some cases, additional molecular testing may be necessary to fully characterize cytogenetic abnormalities.

Transfusion Dependency

The third component of WPSS is transfusion dependency, which reflects both disease severity and its impact on patient quality of life. Transfusion dependency is defined as requiring at least one red blood cell transfusion every 8 weeks over a period of 4 months. This criterion is assigned 1 point if present and 0 points if absent.

Transfusion dependency is a clinically relevant factor that captures several important aspects of MDS:

• Disease Severity: Patients requiring regular transfusions typically have more severe anemia, which often correlates with more advanced disease.
• Quality of Life: Transfusion dependency significantly impacts patient quality of life, requiring frequent medical visits and carrying risks of transfusion-related complications.
• Iron Overload: Regular transfusions lead to iron accumulation, which can cause organ damage over time, particularly affecting the heart, liver, and endocrine organs.
• Prognostic Significance: Transfusion dependency has been shown to be an independent prognostic factor, even after accounting for other disease characteristics.

The dynamic nature of transfusion dependency is particularly important. A patient who becomes transfusion-dependent during the course of their disease will have their WPSS score increase, reflecting the progression of their condition. Conversely, effective treatment that eliminates transfusion dependency can lower the WPSS score, demonstrating the system's responsiveness to clinical changes.

Calculating the WPSS Score

The WPSS score is calculated by summing the points from all three components:

• WHO Classification: 0-3 points
• Cytogenetic Risk: 0-2 points
• Transfusion Dependency: 0-1 point

This yields a total score ranging from 0 to 6 points. The calculation is straightforward, but it requires accurate assessment of each component. Clinicians must ensure they have:

• Accurate bone marrow morphology assessment for WHO classification
• Comprehensive cytogenetic analysis for risk categorization
• Complete transfusion history to determine dependency status

Risk Stratification

Based on the total WPSS score, patients are stratified into five risk categories, each associated with distinct prognostic outcomes:

Very Low Risk (Score 0)

Patients with a WPSS score of 0 have the most favorable prognosis. This category typically includes patients with RA, RARS, or isolated del(5q) who have good-risk cytogenetics and are not transfusion-dependent. The median survival for this group is approximately 11.6 years, and the risk of progression to AML is relatively low. These patients often require minimal intervention and may be managed with observation or supportive care alone.

Low Risk (Score 1)

Patients with a WPSS score of 1 have a good prognosis, though not as favorable as the very low-risk group. This category may include patients with RCMD who have good cytogenetics, or patients with RA/RARS who have intermediate cytogenetics or are transfusion-dependent. The median survival is approximately 5.2 years. These patients may benefit from disease-modifying therapies, particularly if they are symptomatic or have cytopenias affecting quality of life.

Intermediate Risk (Score 2)

Patients with a WPSS score of 2 fall into an intermediate prognostic category. This may include patients with RAEB-1 and good cytogenetics, or patients with lower-risk WHO classifications but poor cytogenetics or transfusion dependency. The median survival is approximately 2.8 years. These patients often require more aggressive management strategies and may be candidates for disease-modifying therapies or, in some cases, allogeneic hematopoietic stem cell transplantation.

High Risk (Score 3-4)

Patients with WPSS scores of 3-4 have a poor prognosis. This category typically includes patients with RAEB-1 or RAEB-2 who have intermediate or poor cytogenetics, often combined with transfusion dependency. The median survival is approximately 1.6 years. These patients require aggressive treatment approaches, and allogeneic hematopoietic stem cell transplantation should be strongly considered for eligible patients. Disease-modifying therapies, including hypomethylating agents, are often indicated.

Very High Risk (Score 5-6)

Patients with WPSS scores of 5-6 have the poorest prognosis. This category typically includes patients with RAEB-2 who have poor cytogenetics and are transfusion-dependent. The median survival is approximately 0.8 years. These patients have a very high risk of progression to AML and require immediate, aggressive intervention. Allogeneic hematopoietic stem cell transplantation should be urgently considered for eligible patients, and disease-modifying therapies should be initiated promptly.

Clinical Applications

Treatment Decision-Making

The WPSS plays a crucial role in guiding treatment decisions for MDS patients. The risk category determined by WPSS helps clinicians select appropriate therapeutic strategies:

• Very Low and Low Risk: These patients may be managed with observation, supportive care (including transfusions and growth factors), or disease-modifying therapies such as lenalidomide (for del(5q)) or erythropoiesis-stimulating agents. The goal is to maintain quality of life while minimizing treatment-related toxicity.
• Intermediate Risk: These patients often benefit from disease-modifying therapies, including hypomethylating agents (azacitidine or decitabine). Allogeneic hematopoietic stem cell transplantation may be considered, particularly for younger patients with good performance status.
• High and Very High Risk: These patients require aggressive intervention. Hypomethylating agents are often the first-line treatment, with allogeneic hematopoietic stem cell transplantation being the only potentially curative option. The timing of transplantation is critical, and referral to a transplant center should occur early in the disease course.

Dynamic Risk Assessment

One of the key advantages of WPSS is its dynamic nature. Unlike static scoring systems that can only be applied at diagnosis, WPSS can be recalculated at any point during the disease course. This allows clinicians to:

• Monitor Disease Progression: An increase in WPSS score over time may indicate disease progression and the need for more aggressive therapy.
• Assess Treatment Response: A decrease in WPSS score following treatment (for example, if a patient becomes transfusion-independent) indicates a favorable response and may guide continued therapy.
• Reevaluate Prognosis: Regular recalculation of WPSS allows for ongoing prognostic assessment, which is particularly important given the variable clinical course of MDS.
• Guide Timing of Interventions: Changes in WPSS score can help determine the optimal timing for interventions such as hematopoietic stem cell transplantation.

Patient Counseling

The WPSS provides valuable information for patient counseling. By understanding their risk category and associated prognosis, patients can:

• Make informed decisions about treatment options
• Understand the expected disease course
• Plan for future medical needs
• Participate in shared decision-making with their healthcare team

However, it is important to emphasize that WPSS provides population-based estimates and that individual patient outcomes may vary. Factors such as age, performance status, comorbidities, and patient preferences must also be considered in treatment decisions.

Comparison with Other Scoring Systems

WPSS vs. IPSS

The International Prognostic Scoring System (IPSS) was the predecessor to WPSS and remains widely used. Key differences include:

• Static vs. Dynamic: IPSS can only be applied at diagnosis, while WPSS can be used throughout the disease course.
• Classification System: IPSS uses the FAB (French-American-British) classification, while WPSS uses the more detailed WHO classification.
• Transfusion Dependency: WPSS incorporates transfusion dependency, which is not included in IPSS.
• Cytogenetic Categories: Both systems use cytogenetic risk, but the categorization may differ slightly.

In general, WPSS provides more refined risk stratification, particularly for lower-risk patients, and its dynamic nature makes it more useful for ongoing patient management.

WPSS vs. IPSS-R

The Revised International Prognostic Scoring System (IPSS-R) was developed after WPSS and incorporates some similar concepts, including more detailed cytogenetic risk stratification. However, IPSS-R remains a static system that can only be applied at diagnosis. WPSS's unique advantage is its dynamic nature, allowing for reassessment throughout the disease course.

Limitations and Considerations

Technical Limitations

Several technical factors can affect the accuracy of WPSS calculation:

• Quality of Cytogenetic Analysis: Accurate cytogenetic risk assessment requires high-quality karyotypic analysis. Inadequate sampling or suboptimal laboratory techniques can lead to misclassification.
• Bone Marrow Morphology: Accurate WHO classification depends on expert morphological assessment. Inter-observer variability in morphological interpretation can affect classification accuracy.
• Transfusion History Documentation: Accurate assessment of transfusion dependency requires complete and accurate medical records. Incomplete documentation can lead to misclassification.

Clinical Limitations

WPSS has several clinical limitations that must be considered:

• Population-Based Estimates: WPSS provides population-based survival estimates. Individual patient outcomes may vary significantly based on factors not captured in the scoring system, such as age, performance status, comorbidities, and response to therapy.
• Treatment Effects: The original WPSS validation was performed in a specific patient population with particular treatment patterns. Outcomes may differ in patients receiving newer therapies or different treatment approaches.
• Missing Factors: WPSS does not incorporate all potentially relevant prognostic factors, such as molecular mutations (e.g., TP53, ASXL1, SRSF2), which have been shown to have prognostic significance in MDS.
• Age and Comorbidities: WPSS does not directly account for patient age or comorbidities, which can significantly impact treatment decisions and outcomes.

Evolving Landscape

The field of MDS continues to evolve, with new molecular insights and treatment options emerging regularly. While WPSS remains a valuable tool, clinicians should be aware of:

• Molecular Markers: Next-generation sequencing has identified numerous molecular mutations with prognostic significance in MDS. Future prognostic systems may incorporate these molecular markers.
• New Therapies: The introduction of new therapeutic agents, such as luspatercept and other novel agents, may alter the natural history of MDS and affect the prognostic significance of WPSS components.
• Updated Classifications: The WHO classification system continues to be refined, and future updates may affect WPSS scoring.

Practical Implementation

When to Calculate WPSS

WPSS should be calculated:

• At initial diagnosis, after complete diagnostic workup including bone marrow examination and cytogenetic analysis
• When significant clinical changes occur (e.g., development of transfusion dependency, progression to higher-risk WHO classification)
• Following treatment interventions to assess response
• At regular intervals during follow-up (e.g., every 6-12 months) to monitor disease course
• When considering changes in treatment strategy

Required Information

To accurately calculate WPSS, clinicians need:

• Bone Marrow Morphology Report: Including blast percentage and assessment of dysplasia in different cell lines to determine WHO classification
• Cytogenetic Report: Complete karyotypic analysis to determine cytogenetic risk category
• Transfusion History: Detailed record of red blood cell transfusions over the preceding 4 months to determine transfusion dependency

Integration with Clinical Practice

WPSS should be integrated into clinical practice as one component of comprehensive MDS management. It should be used in conjunction with:

• Clinical assessment of patient symptoms and quality of life
• Evaluation of performance status and comorbidities
• Assessment of treatment goals and patient preferences
• Consideration of available treatment options and their expected outcomes
• Regular monitoring of disease progression and treatment response

Future Directions

The field of MDS prognostication continues to evolve, and several areas of ongoing research may influence future versions of prognostic scoring systems:

• Molecular Profiling: Integration of molecular mutations into prognostic systems may provide more refined risk stratification. Mutations in genes such as TP53, ASXL1, SRSF2, U2AF1, and others have been shown to have prognostic significance.
• Gene Expression Profiling: Patterns of gene expression may provide additional prognostic information beyond cytogenetics and morphology.
• Biomarkers: Serum biomarkers and other laboratory parameters may be incorporated into future prognostic systems.
• Treatment Response Prediction: Future systems may incorporate factors that predict response to specific therapies, allowing for more personalized treatment selection.
• Quality of Life Metrics: Incorporation of patient-reported outcomes and quality of life measures may provide a more comprehensive assessment of disease impact.

Despite these potential future developments, WPSS remains a valuable and widely used tool in clinical practice. Its dynamic nature, incorporation of clinically relevant factors, and proven prognostic value make it an essential component of MDS management.