Incidence

• Estimated incidence of 2:1,000,000 per year in Western Hemisphere and Europe with increased incidence of 5 to 7:1,000,000 per year in Far East and those of Asian descent
• In the pediatric population, most commonly presents between ages 15 and 25 years.

Genetics

Patients with a number of inherited bone marrow failure syndromes are at increased risk of developing aplastic anemia. Recent evidence implicates somatic clonal mutations of genes involved in immune regulation and cellular proliferation in acquired aplastic anemia.

Initial Tests (screening, lab, imaging)

• To confirm the diagnosis:
  • In aplastic anemia, evaluation of the bone marrow and blood counts reveal:
    • Empty or hypoplastic bone marrow
    • Two out of three of the following:
      • Absolute neutrophil count (ANC) <1,500/μL
      • Platelets <50,000/μL
      • Hemoglobin (Hgb) <10 g/dL
  • Severe aplastic anemia (sAA) is characterized by more severe cytopenias:
    • Bone marrow cellularity <25%
    • Two out of three of the following:
      • ANC <500/μL
      • Platelets <20,000/μL
      • Absolute reticulocyte count <20,000/mL
  • Very severe aplastic anemia: The criteria are the same as for sAA, except for ANC <200/μL.
• To diagnose idiopathic aplastic anemia, one must search for and exclude other secondary causes for the aplasia. To exclude other causes:
  • Complete blood count, manual differential, and reticulocyte count
  • Peripheral blood smear to look at morphology
  • Hgb F %
  • Liver function tests, lactate dehydrogenase (LDH), uric acid
  • Direct and indirect Coombs assay
  • Serum iron, ferritin, total iron-binding capacity (TIBC)
  • Flow cytometry for glycosylphosphatidylinositol (GPI)-anchored proteins CD55/CD59
  • Vitamin B₁₂, folate, copper, zinc levels
  • Viral studies: hepatitis A, B, and C; EBV, CMV, HIV, HHV-6, varicella-zoster virus (VZV), parvovirus
  • Antinuclear antibody (ANA), anti–double stranded DNA (dsDNA) antibody
  • Acid-fast bacillus (AFB) staining of bone marrow aspirate
  • Screening for inherited bone marrow failure syndromes:
    • Diepoxybutane (DEB) chromosomal breakage test (Fanconi anemia)
    • Telomere length (dyskeratosis congenita)
    • Exocrine pancreatic testing via serum trypsinogen and pancreatic isoamylase (Shwachman-Diamond syndrome)
    • Erythrocyte adenosine deaminase level (Diamond-Blackfan anemia)
    • c-MPL mutation (congenital amegakaryocytic thrombocytopenia)
    • Targeted panels for known inherited marrow failure syndrome mutations
• Imaging
  • Chest radiograph to examine for mediastinal mass or lymphadenopathy
  • Abdominal ultrasound if suspicion for organomegaly/mass
  • Echocardiogram if dysmorphic features are present or if concern on exam for cardiac anomaly

Diagnostic Procedures/Other

• Bone marrow aspirate and biopsy for morphology and tissue architecture
  • Bone marrow fragments are hypocellular with prominent fat spaces and reduced erythropoiesis and granulopoiesis. Lymphocytes, macrophages, plasma cells, or mast cells may be prominent.
  • Increased blasts, hypercellularity, prominent reticulin staining, or dysplasia in any lineage is not consistent with a diagnosis of aplastic anemia.
• Flow cytometry of bone marrow to evaluate for leukemia
• Cytogenetics of bone marrow with fluorescence in situ hybridization (FISH) for monosomy 5, 7

First Line

In children and young adults with sAA, the treatment of choice is hematopoietic cell transplant (HCT) with a matched sibling donor (MSD). This curative approach results in a higher success rate, and a lower relapse risk, than immune suppressive therapy (IST). MSD HCT for sAA is often performed with cyclophosphamide and antithymocyte globulin (ATG) conditioning. Because outcomes are best when performed before prolonged periods of transfusion support, prompt HLA typing of the patient and any potential sibling donors is essential.

Second Line

For patients without an MSD, multiple treatment options are available, each with unique risks and benefits:

• IST with combination horse ATG (hATG) and cyclosporine (CsA) followed by a prolonged taper of CsA. Clinical improvement is seen in two thirds of patients, but relapse is common (30–60% of responders). For those without clinical improvement in 3 to 6 months, consider an alternative therapy.
• Alternative donor HCT is becoming more common in pediatric sAA but is typically not offered as initial treatment outside of a clinical trial. Alternative donor HCT is often used for patients who didn’t respond to or relapsed after IST, but outcomes are not as good when HCT is performed after the accumulation of organ toxicities and alloimmunization.
• High-dose cyclophosphamide is a non-HCT treatment option that works by targeting the autoreactive T-cells involved in sAA pathophysiology, followed by a period of pancytopenia and then ultimately autologous reconstitution. This treatment is newer but is becoming more widespread and has yet to be compared prospectively with other treatment options.

Patient Monitoring

• Those who undergo HCT are expected to have hematopoietic reconstitution as they engraft. Hematologic recovery in those who undergo IST may take several months: 90% of patients who respond will do so by 3 months, but some patients may take up to 6 months from ATG to recover marrow function.
• Parameters of recovery
  • Improve overall hematopoiesis to reduce transfusion dependency and no longer fulfill criteria for sAA by 6 months. Neutrophils may be the first lineage to improve.
  • Relapse or clonal evolution commonly occurs at 2 to 4 years from time of IST. Some centers recommend monitoring bone marrow aspirates with biopsy at 6-month intervals for 1st year after IST and then annually.