What are the diagnostic criteria and treatment options for aplastic anemia?

Diagnosis and Treatment of Aplastic Anemia

Bone marrow biopsy is the cornerstone of aplastic anemia diagnosis, which requires demonstration of hypocellular marrow (<20%) with peripheral pancytopenia in the absence of dysplasia or abnormal cell clusters. 1

Diagnostic Criteria

Essential Diagnostic Tests

1. Peripheral Blood Assessment:

   • Complete blood count showing pancytopenia
   • Count at least 100 cells on peripheral blood film
   • Assess for presence of blasts (absent in aplastic anemia)
   • Evaluate for granulocyte dysplasia (minimal/absent in aplastic anemia)
   • Red blood cell distribution width (helps differentiate from hypocellular MDS) 2
   • Absolute lymphocyte and reticulocyte counts 2

2. Bone Marrow Evaluation:

   • Bone marrow aspirate:

     • Perform 500 cell differential when possible
     • Examine for dysplasia (should be minimal/absent)
     • Iron stain to rule out ring sideroblasts (>5 granules around nuclear membrane excludes aplastic anemia) 1

   • Bone marrow biopsy (critical and necessary):

     • Assess cellularity (typically <20% in severe cases)
     • 1-2 cm core biopsy preferred
     • Age-adjusted cellularity assessment is essential
     • Absence of abnormal localization of immature precursors (ALIP)
     • Perform reticulin stain to assess fibrosis

3. Additional Studies:

   • Cytogenetics/FISH (clonal abnormalities more common in MDS)
   • Flow cytometry
   • PNH screening by sensitive flow cytometry
   • Rule out inherited bone marrow failure syndromes 3

Diagnostic Accuracy

• Single bone marrow aspirate plus peripheral blood: ~54% diagnostic accuracy
• Adding bone marrow biopsy: ~95% diagnostic accuracy
• Multiple-site bone marrow examination: required in ~5% of cases 2

Treatment Options

First-Line Treatment Decision Algorithm

1. Determine transplant eligibility:

   • HLA typing should be done at diagnosis for all patients
   • Consider bone marrow transplantation as first-line therapy when available 4

2. Donor priority for transplantation:

   • HLA-identical sibling
   • HLA-matched unrelated donor
   • HLA-haploidentical donor 4

3. For patients unsuitable for bone marrow transplantation:

   • Anti-thymocyte globulin (ATG):

     • Dosage: 10-20 mg/kg daily intravenously for 8-14 days
     • Additional alternate-day therapy up to 21 total doses may be given
     • Monitor for anaphylaxis during infusion and for 24 hours after 5

   • Combination therapy options:

     • ATG + Cyclosporine A (effectiveness rate ~78%, 5-year survival ~74%) 2
     • Cyclosporine A + Androgen therapy (effectiveness rate ~59%, 5-year survival ~77%) 2
     • Consider adding eltrombopag to standard immunosuppressive therapy 3

4. For severe aplastic anemia with insufficient response to immunosuppressive therapy:

   • Eltrombopag:
     • Starting dose: 36 mg orally once daily (18 mg for East/Southeast Asian patients or those with hepatic impairment)
     • Adjust dose based on platelet count response
     • Maximum dose: 54 mg daily 6

Key Distinctions from Similar Conditions

Differentiating from Hypocellular MDS

• Absence of dysplasia in erythroid precursors, granulocytes, and megakaryocytes
• No abnormal sideroblasts
• Absence of ALIP (clusters of immature precursors)
• Normal cytogenetics (clonal abnormalities present in ~32% of hypocellular MDS vs ~4% in aplastic anemia) 2
• Different red blood cell distribution width and absolute lymphocyte/reticulocyte counts 2

Pitfalls to Avoid

1. Diagnostic pitfalls:

   • Relying solely on bone marrow aspirate (inadequate in hypocellular marrow)
   • Failure to perform age-adjusted cellularity assessment
   • Missing focal areas of dysplasia or blast clusters (requires thorough examination)
   • Not excluding secondary causes (myelotoxic agents, radiation exposure)

2. Treatment pitfalls:

   • Delaying HLA typing and donor search
   • Using androgen monotherapy (effectiveness rate only ~25%) 2
   • Failing to monitor for hepatotoxicity with eltrombopag
   • Not screening for PNH clone, which may influence treatment decisions

Monitoring and Follow-up

• Weekly complete blood counts with differentials until stable platelet count
• Monthly complete blood counts thereafter
• Regular liver function tests during immunosuppressive therapy
• MRI may be useful for monitoring bone marrow repopulation after transplantation 7
• Long-term monitoring for disease relapse and development of clonal disorders (MDS/AML) in patients treated with immunosuppressive therapy 4