Management

Patients with aplastic anemia often come into recognition when symptoms of pancytopenia are present. It is
important to recognize the cytopenias because they may lead to life threatening events. Supportive management is
thus initiated first to address the immediate problems associated with pancytopenia before proceeding with the
definitive management.
Supportive Management
The major consequences of cytopenias include decompensation in severe anemia, haemorrhage resulting from
thrombocytopenia, and infections due to leukopenia. The goals of supportive care are directed towards these
events. Anemia and thrombocytopenia are usually addressed with transfusions, and broad spectrum antibiotics are
usually given for infections.
Transfusions with blood components such as red cells and platelets are given to maintain blood counts. The initial
goal of transfusion therapy for anemia should be to correct or avoid cardiopulmonary complications. Red cell
transfusions are given to maintain a safe haemoglobin level of >80 g/l, although this will depend on co-morbidities.
The goal of platelet transfusion should be to maintain a high enough platelet count to prevent spontaneous
bleeding. Prophylactic platelet transfusions are indicated when the platelet count is < 10 x 109 /L (< 5 x 109 /L) or
< 20 x 109 /L in the presence of fever, or infection. Prediction of bleeding is often a challenge and fatal
haemorrhage, such as sudden cerebral haemorrhage can occur without warning and may even be the presenting
manifestation.
Problems may arise due to multiple transfusions sucha s alloimunisation and iron overload. Patients with aplastic
anaemia may develop alloimmunisation to leucocytes present in red cell and platelet transfusions by generating
HLA or nonHLA (minor histocompatibility) antibodies. The use of leukoreduced blood products is recommended to
prevent HLA alloimmunisation. Non-sensitized patients can receive random donor platelets while allo-sensitized
patients with platelet refracoriness should receive HLA- and/or HPA-matched platelet concentrates. Blood products
should also be irradiated to prevent transfusion associated graft-versus-host disease reduction of sensitization to
HLA and non-HLA antigens from multiple transfusions. Iron overload can cause significant problems in heavily
transfused patients. Iron chelation is generally effective in reducing iron burden in AA. Reduction in serum ferritin is
a function of transfusional iron intake and dose of chelator such as desferroxamine or deferasirox.
Growth factors are an option for patients who need support for hematopoiesis, but currently there are no effective
and safe haemopoietic growth factors to support red cell and platelet counts in patients with aplastic anaemia.
There is no standardized approach to antibiotic therapy in these patients. As for all neutropenic patients, fever may
require immediate hospitalisation and treatment before the results of bacterial investigations are available. A
combination of antibiotics must be employed wherein the exact choice depends on local hospital microbiological
sensitivity/resistance patterns. It is recommended that systemic antifungal therapy is introduced into the febrile
neutropenia regimen early if fevers persist.
The risk of infection is determined by the patients neutrophil and monocyte counts, and on an individual basis as
some patients have repeated infections. Patients with aplastic anaemia are at risk of bacterial and fungal infections.
Severely neutropenic (<0.5x10^9/L) patients should receive prophylactic antibiotics to help prevent Gram-negative
sepsis with either a combination of two non-absorbable antibiotics, such as neomycin and colistin, or a quinolone
antibiotic, such as ciprofloxacin. These patients are also at high risk of fungal infection, including Aspergillus.
Fluconazole provides no cover against Aspergillus species. The drugs of choice are itraconazole and posaconazole.

Definitive Management
Initially, infection or uncontrolled bleeding should be treated first before giving immunosuppressive therapy. This
also applies to patients scheduled for Bone Marrow Transplant (BMT), although it may sometimes be necessary to
proceed straight to BMT in the presence of severe infection as a BMT may offer the best chance of early neutrophil
recovery. It is essential that before specific treatment is given, the patient is stabilized clinically in terms of
controlling bleeding and treating infection. It is dangerous to give immunosuppressive therapy; since, the presence
of infection is an adverse factor for outcome after stem cell transplantation. Prednisolone should not be used to
treat patients with aplastic anemia, because corticosteroids are ineffective, they encourage bacterial and fungal
colonization, and can precipitate GI hemorrhage. Similarly, hematopoietic growth factors, such as G-CSF and

rHuEpo, should not be used on their own in newly diagnosed patients in the mistaken belief that they may cure the
disease. This would lead to a delay in giving specific treatment, during which time the patient may become
infected or allo-immunised.
Hematopoietic stem cell transplantation- Bone marrow transplantation is potentially curative and is the treatment of
choice for treatment for children and young adults (age < 30 years) with Severe Aplastic Anemia who have an HLAmatched sibling donor. An advantage of BMT over the standard Immunosuppressive therapy (IST) is a marked
reduction both in the risk of relapse and the evolution of late clonal disorders such as MDS and PNH.
Cyclophosphomide with or with antithymocyte globulin (ATG) is commonly used for conditioning before BMT in
patients with SAA. Although this regimen is non-myeloablative, the immunosuppression is sufficient to allow
engraftment in most cases. Avoidance of total body irradiation (TBI) and busulfan markedly reduces transplantrelated complications such as mucositis, GVHD, second malignancies and infertility.
Treatment Algorithm for Newly Disgnosed Severe AA

Compared with BMT, another highly effective treatment for SAA is Antithymocyte globulin (ATG) and Cyclosporine A
(CsA) Immunosuppressive therapy (IST), and is generally first-line therapy for SAA patients who lack matched
sibling donors or are not good candidates for BMT. The hematopoietic response rate after ATG/CsA is 60-70% and
the probability of survival at 5 years ranges from 60 to 85%. However, up to 40% eventually relapse.
In a prospective randomized controlled trial of the IST for Non-severe Aplastic Anemia, showed that the combination
of ATG and CsA resulted in a significantly higher median hemoglobin level and platelet count at 6 months.
Treatment Algorithm for Newly Diagnosed Non-Severe AA

Tacrolimus as an alternative to CsA has been investigated in children with SAA and found to have comparable
response rates (88 vs 85%) with a more favorable side effect profile.
The decision whether to use ATG in older patients can be difficult and requires careful assessment and discussion of
the risks with the patient. For older patients, the response rate and survival rate are lower compared to younger
patients. Older patients (aged > 60 years) also have a higher risk of serious cardiac events after ATG.
References:
https://www.ebmt.org/Contents/Resources/Library/Slidebank/AACQEventNov2012/Documents/AA03_Su
pportiveCare_SchrezenmeierFinal.pdf
http://aphcon.org/aplastic-anemia-treatment-guidelines.html
http://www.bcshguidelines.com/documents/Aplast_anaem_bjh_june2010.pdf
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3138728/