Case 148 conclusion and summary

The patient is treated for serum sickness. Given the severity of the symptoms, he is given another pulse of methylprednisolone and converted back to oral prednisolone. He is also treated supportively with analgesia and antipyretics, as well as platelet transfusions. He makes a gradual improvement over the next week and is discharged with a slower taper of his prednisolone. He continues on ciclosporin with trough level monitoring. Two months later, he shows early signs of treatment response with a slowly improving neutrophils count. By 6 months, he is transfusion independent and bone marrow biopsy shows improving trilineage haematopoiesis. A slow taper of his ciclosporin is commenced and he remains under close outpatient follow up.

Aplastic Anaemia

Definition: pancytopenia with bone marrow hypoplasia

Aetiology:
Constitutional syndromes
Fanconi anaemia
Dyskeratosis congenital
Shwachman-Diamond syndrome

Marrow toxicity
Myeloablative chemotherapy/radiotherapy
Industrial toxic exposures, e.g. benzene, radiation accidents

Immune-mediated
Idiopathic (most common)
Idiosyncratic drug reactions (e.g. chloramphenicol)
Viral, e.g. HIV, hepatitis viruses
Associated conditions: sero-negative hepatitis, thymoma, eosinophilic fasciitis

Clinical features:
Symptoms/signs related to pancytopenia
If constitutional, then may have congenital abnormalities associated with underlying syndrome (e.g. developmental delay, short stature, etc.)
If associated PNH, then may have features of haemolysis or thrombosis
Clonal evolution (MDS, AML) – although usually a late complication rather than presenting feature

Diagnostic work-up:
Detailed clinical history and examination, including family history, drug history, toxic exposures
FBC with reticulocyte count and blood film
Haemolysis screen
B12 and folate
Autoantibody screen
Viral serology – EBV, CMV, HIV, parvovirus, hepatitis A-E
CT scan if concerns re: underlying malignancy, especially lymphoid

Bone marrow aspirate and trephine biopsy
Cytogenetics on marrow aspirate
PNH screen (peripheral blood flow cytometry)
Chromosomal breakage analysis
Further investigations for constitutional syndromes depends on degree of suspicion

Diagnostic criteria:

  1. Pancytopenia
  2. Marrow hypocellularity (<25% cellularity)
  3. No marrow fibrosis or abnormal infiltrate

Severe AA: at least two of neutrophils <0.5, platelets <20, reticulocytes <20
Very severe AA: as for severe AA but neutrophils <0.2
Non-severe: cytopenias do not meet criteria for severe or very severe AA

Other differentials for pancytopenia with hypoplastic marrow:
Hypoplastic MDS/AML
PNH
Lymphoma
Mycobacterial infections
Primary myelofibrosis

Treatment of severe/very severe acquired aplastic anaemia

Supportive care

Red cell and platelet transfusions
Consider phenotype red cells to reduce risk of alloimmunisation
Consider prophylactic antimicrobials in severely neutropenic patients (follow local guidelines)
Antibiotics for neutropenic sepsis

Immunosuppressive therapy
Horse ATG and ciclosporin
Pros:
1. Avoids transplant-related morbidity/mortality
2. Option in patients without BM donor
Cons:
1. Delayed response (3-4 months)
2. Less effective than stem cell transplantation
3. Adverse effects, e.g. serum sickness with ATG
4. Risk of clonal evolution to MDS and AML in longterm

Allogeneic stem cell transplantation
Treatment of choice for younger, fit patients with matched sibling donor
Matched unrelated donor an option for patients who fail to respond to immunosuppressive therapy
Pros:
1. Higher response/cure rate
2. Reduced risk of clonal evolution
3. More rapid response
Cons:
1. Transplant-related morbidity/mortality, esp. infection and GvHD
2. Small risk of graft failure
3. Need a donor

Treatment of older patients
Depending on fitness, options include:
1. ATG and ciclosporin
2. Ciclosporin alone
3. Eltrombopag for refractory disease
4. Best supportive care only

Prognosis:
Significantly improved over the last few decades
Untreated – one year mortality as high as 70%
With current treatment (in younger, fit patients) – long-term survival can be as high as 80-90%

References
Guidelines for the diagnosis and management of adult aplastic anaemia, BSH. https://onlinelibrary.wiley.com/doi/full/10.1111/bjh.13853

Aplastic anemia, NEJM. https://www.nejm.org/doi/full/10.1056/nejmra1413485

How I treat acquired aplastic anemia, Blood. https://ashpublications.org/blood/article/129/11/1428/35931/How-I-treat-acquired-aplastic-anemia

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