At what point does a low-grade Myelodysplastic Syndrome (MDS) progress to a higher grade in an adult patient, typically over 65 years old, with a history of MDS?

Progression from Low-Grade to Higher-Grade MDS

Low-grade MDS progresses to higher-grade disease when bone marrow blast percentage increases from <5% to 5-9% (RAEB-1) or 10-19% (RAEB-2), or when IPSS risk category advances from low/intermediate-1 to intermediate-2/high risk based on worsening cytopenias, evolving cytogenetic abnormalities, or increasing blast count. 1

Specific Blast Thresholds Defining Progression

The WHO classification provides clear morphological cutoffs for disease progression 1:

• Lower-risk MDS: <5% bone marrow blasts (includes refractory anemia, refractory anemia with ring sideroblasts, refractory cytopenia with multilineage dysplasia) 1
• RAEB-1 (higher-risk): 5-9% bone marrow blasts 1
• RAEB-2 (higher-risk): 10-19% bone marrow blasts 1
• Acute myeloid leukemia: ≥20% blasts (no longer classified as MDS) 1

Progression occurs when serial bone marrow examinations demonstrate an increase in blast percentage crossing these thresholds. 1

IPSS Risk Category Progression

Beyond blast count, progression is defined by movement between IPSS risk categories 1:

• Lower-risk disease: IPSS low and intermediate-1 1
• Higher-risk disease: IPSS intermediate-2 and high 1

The IPSS-R stratifies patients into five groups (very low, low, intermediate, high, very high risk) based on three main prognostic factors 1:

• Percentage of bone marrow blasts
• Number and severity of cytopenias
• Specific cytogenetic abnormalities

Progression occurs when recalculation of IPSS-R score shows movement to a higher risk category. 1

Clinical Indicators of Disease Progression

Worsening Cytopenias

Increasing transfusion dependence, particularly development of red blood cell transfusion dependence in previously transfusion-independent patients, signals disease progression. 1 Development of severe thrombocytopenia or neutropenia beyond baseline also indicates advancing disease 1.

Cytogenetic Evolution

Acquisition of new chromosomal abnormalities or evolution to complex karyotype (≥3 abnormalities) represents clonal evolution and disease progression. 1 Specific high-risk cytogenetic changes include abnormalities of chromosomes 5,7, or 17p 1.

Molecular Markers of Progression

Certain somatic mutations indicate imminent progression 1:

• NPM1 mutations and FLT3 duplications are rare in MDS but suggest imminent progression to AML 1
• TP53 mutations (found in ~20% of del(5q) MDS) confer higher risk of AML progression 1
• ASXL1, RUNX1, and TP53 mutations may indicate higher-risk disease 1

Timeline and Risk of Progression

The natural course of MDS is highly variable, with median overall survival of 15-30 months and risk of AML progression of 25-35% at 5 years. 1 However, progression rates differ dramatically by subtype 1:

• RAEB-1: 25% transform to AML within first year, 35% within 2 years 1
• RAEB-2: 55% transform to AML within first year, 65% within 2 years 1
• Refractory anemia with ring sideroblasts: Very low AML progression rate, excellent overall survival, 0% transformation within 2 years 1
• Refractory anemia: 5% transformation in first year, 10% within 2 years 1

Monitoring Strategy for Detecting Progression

Serial bone marrow examinations are essential for detecting progression, though optimal frequency is not standardized. 1 Reasonable approach includes:

• Lower-risk MDS: Bone marrow examination every 6-12 months or when clinical deterioration occurs (worsening cytopenias, new transfusion dependence, constitutional symptoms) 1, 2
• Intermediate-risk MDS: Bone marrow examination every 3-6 months 1
• Complete blood counts should be monitored more frequently (every 1-3 months) to detect worsening cytopenias 2

Critical Pitfalls to Avoid

Do not assume stable peripheral blood counts mean stable disease—blast percentage can increase in bone marrow while peripheral counts remain relatively unchanged. 1 Bone marrow examination is mandatory for assessing progression 1.

Do not delay bone marrow reassessment when patients develop new transfusion dependence, constitutional symptoms (fever, weight loss, night sweats), or worsening cytopenias. 1, 2 These clinical changes may herald progression even before scheduled surveillance.

Recognize that bone marrow failure (infection and hemorrhage) is the leading cause of death in MDS, with more patients dying before overt AML develops. 1 Therefore, progression to higher-risk disease based on worsening cytopenias and cytogenetics is clinically significant even without increased blasts.

Impact on Treatment Strategy

Progression from lower-risk to higher-risk MDS fundamentally changes treatment goals and approach 1:

• Lower-risk disease: Goals are decreasing transfusion needs and preventing progression; treatments include erythropoiesis-stimulating agents, lenalidomide (for del 5q), immunosuppression 1, 2
• Higher-risk disease: Goal is prolonging survival; treatments include hypomethylating agents (azacitidine, decitabine), intensive chemotherapy, allogeneic stem cell transplantation 1, 2

Allogeneic stem cell transplantation should be considered at time of progression to higher-risk disease in appropriate candidates, as it represents the only potentially curative therapy. 1, 2