What does an IPSS score of 5.5 indicate in a myelodysplastic/myeloproliferative neoplasm overlap syndrome and what is the recommended management?

IPSS Score of 5.5 in MDS/MPN: High-Risk Disease Requiring Immediate Transplant Evaluation

An IPSS score of 5.5 places this patient in the "high-risk" category (IPSS score >4.5-6), indicating a median overall survival of approximately 21 months without transplant and median time to AML evolution of 1.6 years, requiring immediate allogeneic hematopoietic stem cell transplantation (HSCT) evaluation if the patient is medically fit. 1

Critical Context: IPSS vs IPSS-R for MDS/MPN

• The traditional IPSS was developed specifically for MDS, not MDS/MPN overlap syndromes, and patients with proliferative CMML (WBC >12,000/mcL) were explicitly excluded from the original IPSS validation cohort. 1
• However, the IPSS-R (revised system) has been validated for use in MDS/MPN overlap syndromes and provides more accurate prognostic stratification with five risk groups instead of four. 1
• An IPSS score of 5.5 corresponds to "high-risk" disease (score >4.5-6 on IPSS-R scale), which carries significantly worse prognosis than lower-risk categories. 1

Prognostic Implications of IPSS 5.5

Survival Outcomes Without Intervention

• Median overall survival: 21 months for high-risk patients (IPSS-R score >4.5-6). 1
• Median time to 25% AML evolution: 1.6 years for this risk category. 1
• This represents a fundamentally poor prognosis requiring disease-modifying therapy rather than supportive care alone. 1

Treatment-Modified Outcomes

• With azacitidine therapy: median survival improves to 25 months in high-risk patients, representing a modest but significant benefit. 1
• With allogeneic HSCT: median survival dramatically improves to 40 months for high-risk patients, representing the only potentially curative option. 1

Immediate Management Algorithm

Step 1: Confirm Risk Stratification

• Verify that IPSS-R scoring (not original IPSS) has been used, as IPSS-R provides superior prognostic discrimination for MDS/MPN overlap syndromes. 1
• Ensure scoring includes: bone marrow blast percentage, refined cytogenetic risk categories (5 groups), and depth of cytopenias (hemoglobin, platelet count, absolute neutrophil count). 1

Step 2: Transplant Eligibility Assessment

• For patients ≤70 years with adequate performance status: immediately initiate HLA typing and unrelated donor search if no matched sibling is available. 2, 3
• Allogeneic HSCT is the only curative therapy and should be pursued urgently in high-risk disease given the short median time to AML evolution. 1, 3, 4

Step 3: Bridge Therapy While Awaiting Transplant

• Initiate azacitidine 75 mg/m²/day subcutaneously for 7 consecutive days every 28 days as bridge therapy if transplant is planned but not immediately available. 1, 3
• Continue for minimum 2-6 cycles to assess response and maintain disease control until transplant. 3
• Azacitidine shows particular benefit in patients with chromosome 7 alterations and other poor-risk cytogenetics common in high-risk MDS/MPN. 3

Step 4: Non-Transplant Candidates

• For patients >70 years or with significant comorbidities precluding transplant: azacitidine remains first-line therapy with continuation for minimum 6 cycles to assess response. 1, 3
• Supportive care alone is inadequate for high-risk disease given the poor natural history. 1

Critical Prognostic Modifiers to Assess

Cytogenetic Risk

• Poor-risk cytogenetics (monosomy 7, complex karyotype ≥3 abnormalities, chromosome 3 abnormalities) further worsen prognosis within the high-risk category. 1
• Very poor cytogenetics (>3 abnormalities) may shift patient to "very high-risk" category (IPSS-R >6) with median survival of only 13 months without transplant. 1

Age and Performance Status

• Age is the single most important patient-related adverse prognostic factor, independent of disease biology, with patients ≥60-65 years having higher risk of treatment complications. 3, 5
• ECOG performance status and cardiovascular comorbidities are critical for determining transplant eligibility and treatment intensity. 5

Molecular Mutations

• TP53 mutations confer extremely poor prognosis and may influence transplant timing and conditioning intensity. 1, 5
• SF3B1 mutations in MDS/MPN-RS-T may indicate a specific overlap subtype with distinct biology and thrombotic risk. 6, 7

Common Pitfalls to Avoid

• Do not delay transplant evaluation in high-risk disease—median time to AML evolution is only 1.6 years, and outcomes worsen significantly after transformation. 1
• Do not use supportive care alone as primary management strategy in high-risk disease—this approach is appropriate only for lower-risk categories (IPSS Low/INT-1). 1
• Do not assume IPSS and IPSS-R scores are interchangeable—IPSS-R provides more refined risk stratification and should be used preferentially. 1
• Do not overlook MDS/MPN-specific features such as monocytosis or proliferative features that may affect prognosis beyond standard IPSS scoring. 6, 7, 8