Diagnosis and Management of Aplastic Anemia
Aplastic anemia requires a comprehensive bone marrow assessment showing severely reduced cellularity (<20% in severe cases), corrected for patient age, with peripheral blood pancytopenia to establish diagnosis and distinguish it from hypocellular variants of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). 1
Diagnostic Approach
Essential Diagnostic Criteria
- Bone marrow biopsy is critical and necessary for diagnosis, showing hypocellular marrow with fatty replacement of normal hematopoietic tissue 1, 2
- Peripheral blood evaluation showing pancytopenia with examination of at least 100 cells to assess for dysplasia of granulocytes and presence of blasts 1
- Bone marrow aspirate with 500 cell differential when possible to examine for dysplasia of erythroid precursors, granulocytes, and megakaryocytes 3
- Iron stain for ring sideroblast assessment to exclude MDS 3
- Blast percentage below 1% in aplastic anemia, distinguishing it from hypocellular MDS and AML 2
Additional Diagnostic Studies
- Standard cytogenetics/interphase FISH to rule out chromosomal abnormalities 3
- Flow cytometry to assess for abnormal phenotypes 3
- PNH screening by sensitive flow or molecular screening technique 3
- Reticulin stain to assess for fibrosis 3
Distinguishing Features from Related Disorders
- Aplastic anemia lacks moderate to severe erythroid dysplasia and abnormal sideroblasts seen in hypocellular MDS 1
- Absence of clusters of immature precursors (ALIP) which are characteristic of hypocellular AML 1
- Age correction is necessary when assessing bone marrow cellularity to avoid misdiagnosis 1, 2
Management Approach
Risk Stratification
- Severity grading determines treatment approach, with classifications of mild, moderate, and severe based on ANC, platelet count, and reticulocyte count 4
First-Line Treatment Options
- For patients younger than 50 years with an HLA-identical sibling donor: Hematopoietic stem cell transplantation is the treatment of choice and possible cure 4, 5
- For patients without a matched donor or those over 40: Immunosuppressive therapy with horse ATG plus cyclosporine A and eltrombopag is the standard regimen 4, 5, 6
Medication Management
- Eltrombopag for refractory severe aplastic anemia:
- Initial dose: 36 mg orally once daily 7
- Dose reduction needed for patients with hepatic impairment and some patients of East-/Southeast-Asian ancestry 7
- Adjust to maintain platelet count greater than 50 x 10^9/L 7
- Maximum dose: 108 mg per day 7
- Take without a meal or with a meal low in calcium (≤50 mg) 7
- Take at least 2 hours before or 4 hours after medications containing polyvalent cations 7
- Monitor for adverse reactions including nausea (33%), fatigue (28%), cough (23%), diarrhea (21%), and headache (21%) 7
Supportive Care
- Transfusion support with irradiated and filtered blood products 4
- Growth factor support as needed 4
- Weekly CBC during initial treatment 4
- For patients on eltrombopag, regular monitoring of liver function tests 4, 7
Clinical Pitfalls and Caveats
- Misdiagnosis between aplastic anemia and hypocellular MDS/AML can lead to inappropriate treatment with significantly different outcomes 1, 2
- Previous genotoxic exposure or therapy must be excluded as they can cause hypocellular marrows resembling aplastic anemia 1
- Careful monitoring for progression to MDS or AML is necessary as the risk is significantly higher than in the general population 2
- In patients receiving eltrombopag, monitor for hepatotoxicity and potential for cytogenetic abnormalities 7
- Without treatment, mortality from severe aplastic anemia approaches 70% within 2 years, emphasizing the importance of prompt diagnosis and treatment 5
- Long-term issues with immunosuppressive therapy include incomplete response, relapse, and progression to myelodysplasia/leukemia 8