What is the best treatment approach for a patient with Myelodysplastic Syndrome (MDS) and trisomy 8?

Treatment of MDS with Trisomy 8

For MDS patients with trisomy 8 as the sole cytogenetic abnormality, immunosuppressive therapy with antithymocyte globulin (ATG) should be strongly considered as first-line treatment, particularly in lower-risk disease, as this specific cytogenetic subgroup demonstrates exceptional response rates of 67% with durable hematologic improvement. 1

Risk Stratification Determines Treatment Strategy

The IPSS-R classification is essential for determining the treatment approach, stratifying patients into lower-risk (IPSS low, intermediate-1; IPSS-R very low, low, intermediate) versus higher-risk (IPSS intermediate-2, high; IPSS-R intermediate, high, very high) categories 2, 3. Trisomy 8 is classified as an intermediate-risk cytogenetic abnormality in the IPSS-R scoring system 2.

Lower-Risk MDS with Trisomy 8

Immunosuppressive Therapy as Preferred First-Line

• ATG therapy achieves complete or partial hematologic response in 67% of patients with de novo MDS harboring trisomy 8 as the sole karyotypic abnormality, with durable reversal of cytopenias and restoration of transfusion independence 1
• Response to ATG is associated with stable increase in the proportion of trisomy 8 bone marrow cells and normalization of the T-cell repertoire, suggesting an autoimmune pathophysiology specific to this cytogenetic subgroup 1
• ATG is most effective in relatively young patients (<65 years) with low-risk MDS, transfusion history <2 years, normal karyotype or trisomy 8, no excess blasts, and possibly those with thrombocytopenia in addition to anemia 2

Alternative Treatments for Lower-Risk Disease

If ATG is not appropriate or fails:

• Erythropoiesis-stimulating agents (ESAs) such as recombinant erythropoietin or darbepoetin achieve 40-60% erythroid response rates when baseline EPO level is <200-500 U/L and transfusion requirements are low 2, 3, 4
• ESA efficacy can be enhanced by adding G-CSF, with responses typically occurring within 8-12 weeks and median duration of approximately 2 years 2
• Hypomethylating agents (azacitidine or decitabine) can achieve RBC transfusion independence in 30-40% of lower-risk patients after ESA failure 2

Higher-Risk MDS with Trisomy 8

Hypomethylating Agents as First-Line

• Azacitidine 75 mg/m² subcutaneously for 7 consecutive days every 28 days (or acceptable 5-2-2 regimen) is the first-line reference treatment for higher-risk MDS, including those with trisomy 8 2, 3
• At least six cycles of azacitidine are required before assessing response, as most patients only respond after several courses 2
• Azacitidine extends survival by up to 74% despite modest complete response rates 3
• Decitabine is FDA-approved for all MDS subtypes including intermediate-1, intermediate-2, and high-risk IPSS groups 5

Allogeneic Hematopoietic Stem Cell Transplantation

• Allogeneic HSCT should be evaluated at diagnosis for all higher-risk patients, as it represents the only potentially curative treatment 2, 3, 4
• In patients with MDS harboring trisomy 8, allogeneic HSCT achieves 51% overall survival at 4 years with 22% cumulative incidence of relapse 6
• Age >50 years, 2 or more additional cytogenetic abnormalities beyond trisomy 8, and high-risk disease at transplant are associated with higher mortality 6
• Patients with only one additional cytogenetic abnormality beyond trisomy 8 have outcomes similar to those with isolated trisomy 8 6
• HSCT can be preceded by chemotherapy or HMA to reduce blast percentage 2

Special Consideration: Associated Inflammatory/Autoimmune Disorders

Behçet's-Like Disease and Other Inflammatory Manifestations

• Trisomy 8 MDS is uniquely associated with inflammatory and autoimmune diseases, particularly Behçet's-like disease (52% of cases), characterized by orogenital aphthosis, skin features, and severe ulcerative ileocecal disease 7, 8
• Other manifestations include inflammatory arthritis (19%), Sjögren's syndrome, autoimmune hemolytic anemia, neutrophilic dermatosis, and vasculitis 7
• Azacitidine targeting the underlying clonal disease achieves complete remission in 5/7 (71%) and partial response in 2/7 (29%) of patients with inflammatory manifestations, making it superior to immunosuppressive therapies alone 7, 8
• Steroid therapy achieves complete response in 35% and partial response in 47% of patients with inflammatory disorders, but mostly sparing therapies are necessary 7
• TNF-α inhibitors and other immunomodulatory therapies are usually ineffective for controlling dysimmune manifestations in trisomy 8 MDS 8

Treatment Algorithm Based on Risk and Cytogenetic Complexity

For isolated trisomy 8 (sole abnormality):

• Lower-risk: ATG first-line → ESAs if ATG fails or not candidate → HMAs if refractory
• Higher-risk: Azacitidine → Allogeneic HSCT if eligible

For trisomy 8 with one additional abnormality:

• Treat as isolated trisomy 8 with similar prognosis 6

For trisomy 8 with ≥2 additional abnormalities:

• Consider higher-risk approach regardless of IPSS score due to poorer prognosis 6
• Prioritize allogeneic HSCT evaluation early 6

Supportive Care Across All Risk Categories

• RBC transfusions (leukocyte-reduced) for symptomatic anemia, with irradiation for potential stem cell transplant candidates 2
• Iron chelation therapy should be initiated when transfusion-dependent, as iron overload increases infection-related mortality 2, 3
• Monitor serum ferritin levels with goal <1000 mcg/L 2
• G-CSF or GM-CSF for neutropenic patients with recurrent or resistant bacterial infections 2
• Platelet transfusions for severe thrombocytopenia or bleeding 2

Critical Pitfalls to Avoid

• Do not assume trisomy 8 MDS will respond poorly to immunosuppression—this cytogenetic abnormality is uniquely associated with excellent ATG response rates 1
• Do not discontinue azacitidine before completing at least six cycles, as responses are often delayed 2
• Do not overlook inflammatory manifestations as unrelated conditions—they are part of the trisomy 8 MDS disease spectrum and respond to treatment of the underlying MDS 7, 8
• Do not use conventional immunosuppressive therapies alone for inflammatory manifestations—target the clonal disease with azacitidine for superior outcomes 8