Aplastic Anemia

A. Idiopathic
B. Constitutional (congenital Fanconi's aplastic anemia)
C. Chemical & physical agents
1. Dose related: chloramphenicol, benzene, ionizing radiation, alkylating
agents, antimetabolites, mitotic inhibitors, anthracyclines, inorganic
arsenical
2. Idiosyncratic: chloramphenicol, phenylbutazone, sulfa drugs, gold
compounds, organic arsenical, insecticides, hydantoin
D. Hepatitis
E. Immunologically mediated aplasia
F. Pregnancy
G. Paraxymal nocturnal hemoglobinuria
H. Misc: SLE, pancreatitis, miliary TB, viral infections, Simmond's disease.

Differential Diagnosis of Severe Aplastic Anemia
Disease Characteristics Notes
Pancytopenia and
hypocellular
marrow due to
hypoplastic MDS
Hypocellular marrow mimics severe
AA, but subtle dysplastic morphologic
features and abnormal cytogenetics
may help distinguish between
hypoplastic MDS and severe AA
The most useful test is
cytogenetics of bone marrow.
However, normal cytogenetics
may be seen in both MDS and
severe AA. If abnormal, a
diagnosis of MDS is favored
Pancytopenia and
hypocellular
marrow due to
paroxysmal
nocturnal
hemoglobinuria
History of hemolytic anemia with
dark urine. Positive PNH test
distinguishes from severe AA
Flow cytometry is most useful
test for detecting the presence or
absence of PNH. Positive urine
hemosiderin in Ham or sucrose
lysis test support diagnosis of
PNH
Pancytopenia and
hypocellular
marrow due to FA
or dyskeratosis
congenita
Presentation in childhood.
Characteristic physical abnormalities,
particularly bony abnormalities
(Fanconi) and skin disease
(dyskeratosis congenita). Abnormal
cytogenetics tests showing
chromosome fragility characteristic of
Patients with FA may evolve into
severe AA. Therefore, all
patients under age 40 with severe
AA should have chromosome
fragility testing done to exclude
FA as cause of severe AA
FA
Pancytopenia due
to severe
megaloblastic
anemia
Deficiencies of vitamin B12 or folic
acid may result in severe
pancytopenia. Bone marrow
aspiration and biopsy result show
cellular marrow
Normal B12, folate, and cellular
bone marrow aspirate and biopsy
result differentiates from severe
AA
Pancytopenia due
to myelophthisic
(marrow invasive)
condition
The bone marrow biopsy shows
cellular marrow with malignant cells,
including acute myelogenous and
lymphoblastic leukemia,
myelodysplastic syndrome, Hodgkin
disease, non-Hodgkin lymphoma, and
multiple myeloma. Occasionally,
metastatic solid tumors for breast,
lung, or other cancers may cause
pancytopenia excluding diagnosis of
severe AA. Physical exam may show
hepatosplenomegaly or
lymphadenopathy, which is rare in
severe AA
Invasion of bone marrow by any
solid tumor or by any
hematologic malignancy may
result in pancytopenia. Review
of blood smear and bone marrow
aspirate and biopsy result
excludes severe AA. Blood
smear may show teardrops,
nucleated erythrocytes, and
immature cells consistent with
marrow-invasive tumor or
leukemia, lymphoma, or chronic
inflammatory disease
Pancytopenia due
to chronic bacterial
or viral infections
Positive serologic test results for
viruses and evidence of hepatitis with
elevated liver function test (AST,
ALT) results suggesting chronic viral
infection from hepatitis B, C,
infectious mononucleus,
cytomegalovirus, or parvovirus. Bone
marrow aspirate and biopsy result
show cellular marrow
Chronic viral diseases,
granulomatous diseases
(tuberculosis), or, rarely,
bacterial infections may cause
pancytopenia with cellular
marrow or may evolve into true
aplastic anemia
Pancytopenia due
to hypersplenism
Blood counts are not usually severely
depressed. Spleen is enlarged.
Frequent hepatomegaly. Cellular
marrow on biopsy
Liver disease commonly
associated with hypersplenism
Autoimmune
pancytopenia
Patients with severe pancytopenia
with maturation arrest due to
antiprogenitor cell or stem cell
antibodies; bone marrow aspirate is
usually cellular
Rare condition caused by anti-
stem cell antibodies
distinguishable by presence of
cellular marrow on biopsy and
evidence of maturation arrest in
all three lineages (12)
AA = aplastic anemia; ALT = alanine aminotransferase; AST = aspartate
aminotransferase; FA = Fanconi anemia; MDS = myelodysplastic syndrome; PNH
= paroxysmal nocturnal hemoglobinuria.


Non-drug Therapy
Consider one of several non-drug therapies for the treatment of severe AA,
depending on the individual clinical situation.
Consider transfusions of packed red blood cells and platelets in certain
clinical situations.
Recognize that allogeneic bone marrow transplantation of a matched related
donor is the treatment of choice for carefully selected patients under age 50.
Use cyclophosphamide with ATG as the preparative regimen of choice for
patients undergoing allogeneic bone marrow transplants with matched
related donors for severe AA.
Use immunosuppressive therapies to prevent and treat acute and chronic
GVHD in patients undergoing allogeneic stem cell transplantation for severe
AA.
Consider allogeneic bone marrow transplantation with matched unrelated
donors or other alternative donors for patients under age 40 who do not have
a matched related donor.
Drug Therapy
Use immunosuppressive therapy as the treatment of choice for patients with severe
AA who are not candidates for allogeneic bone marrow transplantation.
Consider therapy with ATG, with or without cyclosporine, as the treatment
of choice for patients with severe AA who are not candidates for allogeneic
bone marrow transplantation.
Consider other options for patients in whom ATG, cyclosporine, or both
have failed.
Drug Treatment for Severe Aplastic Anemia
ATG or ALG
Action: Immunosuppressive, lyses of T lymphocytes
Dosage: ATG 40 mg/kg iv x 4 days. Alternative schedule 15 mg/kg for 10
days.
For bone marrow transplantation prep: administer as 30 mg/kg qod x 3
doses on day 6, day 4, and day 2 before bone marrow transplantation
ALG: 40 mg/kg iv x 4 days
Benefit: Induces freedom from transfusion in 60%-80% of patients.
Responses occurring 3 weeks to 6 months after ATG
Side Effects: Fevers, chills, initial anaphylactic reaction, serum sickness,
including serositis, skin rashes. Worsens thrombocytopenia, induces positive
Coombs test result Patients should be hospitalized and infusion should be
given with premedication (see table Clinical Use of Antithymocyte Globulin
in Severe Aplastic Anemia) including corticosteroid coverage. Use of a
large-bore iv catheter with an in-line filter recommended. Multiple preps
raised in horses, goats, rabbits are available. Taper off steroid over 4 weeks.
Note: Up to 20% relapse rates. Patients may be retreated with same or
second ATG raised in different animals and should be closely monitored for
anaphylactic reactions. Long-term follow-up studies show that 20%-50% of
ATG responders may develop secondary myelodysplasias, PNH, or both
Cyclosporine
Immunosuppression through modulation of T-lymphocyte function
3-12 mg/kg initial loading dose. Subsequent doses are monitored by
frequent blood levels to keep level at 150-300 ng/mL
Active in inducing responses as a single agent or with ATG in up to 40%-
50% of patients
Renal toxicity, liver toxicity, hypomagnesemia, aggravates hypertension,
rarely may induce seizures
Monitor renal and liver function tests, magnesium and cyclosporine levels
weekly. A useful option as a single agent in patients who cannot tolerate
ATG. Crossover studies show that it is equally as effective as ATG. Usually
administered with ATG
High-dose cyclophosphamide
Immunosuppressive and T-cell lytic agent
50 mg/kg x 4 for a total of 200 mg/kg. Similar dose for bone marrow
transplantation preparative regimen
May induce remissions in untreated patients and patients in whom ATG or
cyclosporine fail, and may prevent long-term bone marrow dyscrasias
Cardiomyopathy, hemorrhagic cystitis, severe cytopenias
At increased risk for fatal infections.
This drug should not be routinely administered outside a transplant center or
a center specializing in treatment of severe AA; should be reserved for
patients in whom less toxic upfront immunosuppressive therapy fails. Data
suggests that cyclophosphamide may prevent long-term myelodysplasias
Androgens oxymetholone (Anadrol-50)
Stimulates stem-cell growth. Increases sensitivity to erythropoietin
1-5 mg/kg qd orally
Randomized studies have shown that androgens are no more beneficial than
supportive care alone and do not enhance the response to
immunosuppressive agents (62). However, occasionally a patient may
respond with increased blood cell production
Hepatotoxic, including jaundice. May induce liver cysts and liver tumors.
Virilizing in females, contraindicated in pregnant females and in patients
with prostate or breast cancer. Increased fluid retention
Liver function should be monitored closely. Androgen therapy is best
reserved for patients who are not candidates for immunosuppressive or bone
marrow transplant therapy or in whom these therapies fail. It is better
tolerated in male patients
High dose methylprednisolone
Lyses, lymphocytes, immunosuppressive
20 mg/kg qd days 1-3, 10 mg/kg qd days 4-7, 5 mg/kg qd days 8-11, 2
mg/kg qd days 12-20, and 1 mg/kg qd until day 30
With maintenance of 0.1-0.2 mg/kg qd. Up to 38% response rates reported
Steroid psychosis, hyperglycemia, hypertension, aseptic necrosis, volume
overload, potassium wasting, and increased risk of fungal infections
Moderate to low doses of corticosteroids are not beneficial and potentially
detrimental. Use of high-dose methylprednisolone may be useful in patients
in whom ATG, cyclosporine, or both fail or who are intolerant of ATG with
increased toxicity. High-dose methylprednisolone should be reserved for
patients in whom ATG and cyclosporine fails and who have no other
options
Hematopoietic growth factors (G-CSF, GM-CSF)
Stimulates committed progenitor cells, increases leukocyte counts
Neupogen G-CSF (5 g/kg qd) or GM-CSF leukine (250 mcg/m2 qd)
A useful adjunct with immunosuppressive therapy, particularly in patients
with threatened infections. May accelerate or temporarily increase
leukocyte counts. Very little evidence that these growth factors induce
permanent remissions
Fever, chills, bone pain, occasional anaphylactic first-dose reactions, fluid
retention
Long-term use of growth factors may potentially induce increased risk for
myelodysplastic syndrome and rarely induces trilineage recovery. Useful in
raising leukocyte counts short term in patients with threatened infections.
Most hematopoietic growth factors have not induced long-term remissions
in severe AA. Occasional response to stem-cell factor (C-kit ligand, an
investigational drug), or IL-3. No evidence that platelet-stimulating growth
factors such as IL-11 and IL-6 are useful in severe AA
Mycophenolate mofetil (CellCept)
T cell inhibition. Potent immunosuppression
1 g po bid
Uncertain
Diarrhea, melena, increases infection risk
Investigational
*AA = aplastic anemia; ALG = antilymphocyte globulin; ATG = antithymocyte
globulin; bid = twice daily;
G-CSF = granulocyte colony-stimulating factor; GM-CSF = granulocyte-
macrophage colony-stimulating factor; iv = intravenous; po = oral;
PNH = paroxysmal nocturnal hemoglobinuria; qod = every other day; qd = once
daily.