Aplastic Anemia

Aplastic anaemia is bone marrow failure with pancytopenia and a hypocellular marrow, without abnormal infiltration or fibrosis.

• Incidence is 2 to 3 per million per year, with peaks at 10 to 25 and over 60 years, and higher rates in East Asia.
• Mechanism is T cell mediated destruction of haematopoietic stem cells, with interferon gamma and TNF involvement.
• Causes: idiopathic (70 to 80%), drugs (chloramphenicol, carbamazepine, sulfonamides, gold, NSAIDs), toxins (benzene), viruses (hepatitis seronegative, EBV, parvovirus B19, HIV), radiation, pregnancy, PNH clones, inherited (Fanconi anaemia, dyskeratosis congenita, Shwachman Diamond).
• Severity (Camitta): severe if marrow cellularity under 25% with two of neutrophils under 0.5 x 10^9/L, platelets under 20 x 10^9/L, reticulocytes under 20 x 10^9/L. Very severe if neutrophils under 0.2 x 10^9/L.
• Complications: infection, bleeding, transfusion iron overload, clonal evolution to PNH, MDS or AML (10 to 15% at 10 years).

• Anaemia symptoms (fatigue, pallor, dyspnoea), bleeding (petechiae, epistaxis, gum bleeding, menorrhagia), recurrent or severe infections, fever.
• No lymphadenopathy or splenomegaly, which suggests an alternative diagnosis.
• Congenital features in inherited disease: short stature, radial anomalies, abnormal skin pigmentation, nail dystrophy, leukoplakia.

• Full blood count: pancytopenia with low reticulocytes, normal or raised MCV.
• Bone marrow aspirate and trephine: hypocellular with fatty replacement, no dysplasia or fibrosis, normal cytogenetics.
• Exclude MDS, hypocellular AML, hairy cell leukaemia, leukaemia, megaloblastic anaemia, HIV, hepatitis, autoimmune disease.
• PNH flow cytometry (GPI deficient clones), chromosome breakage test (diepoxybutane, mitomycin C), telomere length, and genetic panel in patients under 40 or with family history.
• HLA typing of patient and siblings early.
• Baseline: liver tests, hepatitis B and C, HIV, CMV, EBV, B12, folate, ferritin.

Supportive

• Irradiated, leucodepleted, CMV safe blood products; transfuse for haemoglobin under 7 g/dL and platelets under 10 x 10^9/L (under 20 with fever).
• Antimicrobial prophylaxis for neutropenia: levofloxacin 500 mg daily, fluconazole or posaconazole 300 mg daily, aciclovir 400 mg twice daily. Treat fever as neutropenic sepsis (piperacillin tazobactam 4.5 g every 6 hours).
• Iron chelation (deferasirox 20 mg/kg daily) when ferritin exceeds 1000 µg/L after 20 units.
• Avoid offending drugs and NSAIDs.

Definitive

• Matched sibling donor haematopoietic stem cell transplant for age under 40 (cure in 80 to 90%); conditioning with cyclophosphamide 50 mg/kg x 4 days and rabbit antithymocyte globulin (or fludarabine based reduced intensity in older patients).
• Immunosuppression for those without a suitable donor, or over 40:
  • Horse antithymocyte globulin 40 mg/kg/day for 4 days with ciclosporin 5 mg/kg/day (trough 150 to 250 µg/L, continue for 12 months then slow taper) and methylprednisolone 1 to 2 mg/kg to cover serum sickness. Response in 60 to 70% at 6 months.
  • Eltrombopag 150 mg daily (75 mg in East Asians) added to ATG and ciclosporin improves complete response rate; also used for refractory disease (50 to 150 mg daily).
• Second course of ATG (rabbit) or matched unrelated or haploidentical transplant for relapse or refractory disease.
• Danazol or androgens have limited role. Monitor for clonal evolution with annual marrow and cytogenetics.