Background

Aplastic anemia is a syndrome of bone marrow failure characterized by peripheral pancytopenia and
marrow hypoplasia, and mild macrocytosis is observed in association with stress erythropoiesis and an
elevated fetal hemoglobin levels. Paul Ehrlich introduced the concept of aplastic anemia in 1888 when
he studied the case of a pregnant woman who died of bone marrow failure. However, it was not until
1904 that Anatole Chauffard named this disorder aplastic anemia.

Pathophysiology

The theoretical basis for marrow failure includes primary defects in or damage to the stem cell or the
marrow microenvironment.1,2,3 The distinction between acquired and inherited disease may present a
clinical challenge, but more than 80% of cases are acquired. In acquired aplastic anemia, clinical and
laboratory observations suggest that this is an autoimmune disease.
On morphologic evaluation, the bone marrow is devoid of hematopoietic elements, showing largely fat
cells. Flow cytometry shows that the CD34 cell population, which contains the stem cells and the early
committed progenitors, is substantially reduced.2,4 Data from in vitro colony-culture assays suggest
profound functional loss of the hematopoietic progenitors, so much so that they are unresponsive even
to high levels of hematopoietic growth factors.
Little evidence points to a defective microenvironment as a cause of aplastic anemia. In patients with
severe aplastic anemia (SAA), stromal cells have normal function, including growth factor production.
Adequate stromal function is implicit in the success of bone marrow transplantation (BMT) in aplastic
anemia because the stromal elements are frequently of host origin.

The role of an immune dysfunction was suggested in 1970, when autologous recovery was
documented in a patient with aplastic anemia in whom engrafting failed after BMT. Mathe proposed
that the immunosuppressive regimen used for conditioning promoted the return of normal marrow
function. Since then, numerous studies have shown that, in approximately 70% of patients with
acquired aplastic anemia, immunosuppressive therapy improves marrow function.3,5,6,7,8

Immunity is genetically regulated (by immune response genes), and it is also influenced by
environment (eg, nutrition, aging, previous exposure).9,10 Although the inciting antigens that breach
immune tolerance with subsequent autoimmunity are unknown, human leukocyte antigen (HLA)-DR2
is overrepresented among European and United States patients with aplastic anemia, suggesting a
role for antigen recognition, and its presence is predictive of a better response to cyclosporine.
Suppression of hematopoiesis is likely mediated by an expanded population of the following cytotoxic
T lymphocytes (CTLs): CD8 and HLA-DR+, which are detectable in both the blood and bone marrow of
patients with aplastic anemia. These cells produce inhibitory cytokines, such as gamma-interferon and
tumor necrosis factor, which can suppressing progenitor cell growth. Polymorphisms in these cytokine
genes, associated with an increased immune response, are more prevalent in patients with aplastic
anemia. These cytokines suppress hematopoiesis by affecting the mitotic cycle and cell killing by
inducing Fas-mediated apoptosis. In addition, these cytokines induce nitric oxide synthase and nitric
oxide production by marrow cells, which contributes to immune-mediated cytotoxicity and the
elimination of hematopoietic cells.

Constitutive expression of Tbet, a transcriptional regulator that is critical to Th1 polarization, occurs in
a majority of aplastic anemia patients.5 Perforin is a cytolytic protein expressed mainly in activated
cytotoxic lymphocytes and natural-killer cells. Mutations in perforin gene are responsible for some
cases of familial hemophagocytosis11 ; mutations in SAP, a gene encoding for a small modulator
protein that inhibits undefined-interferon production, underlie X-linked lymphoproliferation, a fatal
illness associated with an aberrant immune response to herpesviruses and aplastic anemia. Perforin
and SAP protein levels are markedly diminished in a majority of acquired aplastic anemia cases.
Frequency
United States
No accurate prospective data are available regarding the incidence of aplastic anemia in the United
States. Findings from several retrospective studies suggest that the incidence is 0.6-6.1 cases per
million population; this rate was largely based on data from retrospective reviews of death registries.
International

The annual incidence of aplastic anemia in Europe, as detailed in large, formal epidemiologic studies,
is similar to that in the United States, with 2 cases per million population. Aplastic anemia is thought to
be more common in Asia than in the West. The incidence was accurately determined to be 4 cases per
million population in Bangkok, but it may be closer to 6 cases per million population in the rural areas
of Thailand and as high as 14 cases per million population in Japan, based on prospective studies.
This increased incidence may be related to environmental factors, such as increased exposure to toxic
chemicals, rather than to genetic factors because this increase is not observed in people of Asian
ancestry who are presently living in the United States.
Mortality/Morbidity

The major causes of morbidity and mortality from aplastic anemia include infection and bleeding.
Patients who undergo BMT have additional issues related to toxicity from the conditioning regimen and
graft versus host disease (GVHD).10,12,13,14,15,16 With immunosuppression, aplastic anemia in
approximately one third of patients does not respond. For the responders, relapse and late-onset
clonal disease, such as paroxysmal nocturnal hemoglobinuria (PNH), myelodysplastic syndrome
(MDS), and leukemia, are risks.6,17,18,19
Race

No racial predisposition is reported in the United States. However, the prevalence is increased in the
Far East.
Sex

The male-to-female ratio for acquired aplastic anemia is approximately 1:1, although there are data to
suggest that a male preponderance may be observed in the Far East.
Age

Aplastic anemia occurs in all age groups.

• A small peak in the incidence is observed in childhood because of the inclusion of inherited
marrow-failure syndromes.
• The incidence of aplastic anemia peaks in people aged 20-25 years, and a subsequent peak
is observed in people older than 60 years. The latter peak may be due to the inclusion of
MDSs, which are syndromes of stem-cell failure unrelated to aplastic anemia. These
syndromes must be considered in the differential diagnosis of any marrow-failure syndrome.

Clinical

History

The clinical presentation of patients with aplastic anemia includes symptoms related to the decrease in
bone-marrow production of hematopoietic cells. The onset is insidious, and the initial symptom is
related to anemia or bleeding, although fever or infections are also often noted at presentation.

• Anemia may manifest as pallor, headache, palpitations, dyspnea, fatigue, or foot swelling.
• Thrombocytopenia may result in mucosal and gingival bleeding or petechial rashes.
• Neutropenia may manifest as overt infections, recurrent infections, or mouth and pharyngeal
ulcerations.
• Although the search for an etiologic agent is often unproductive, an appropriately detailed
work history, with emphasis on solvent and radiation exposure should be obtained, as should
a family, environmental, travel, and infectious disease history.
• In the absence of obvious phenotypic features, the presentation of a patient with an inherited
marrow-failure syndrome is subtle, and a thorough family history may first suggest the
condition.
 • With regard to environmental agents, the time course of aplastic anemia and exposure to the
offending agent varies greatly, and only rarely is an environmental etiology identified.

Physical

Physical examination may show signs of anemia, such as pallor and tachycardia, and signs of
thrombocytopenia, such as petechiae, purpura, or ecchymoses. Overt signs of infection are usually not
apparent at diagnosis.

• A subset of patients with aplastic anemia present with jaundice and evidence of clinical
hepatitis.
• Findings of adenopathy or organomegaly should suggest an alternative diagnosis (eg,
hepatosplenomegaly and supraclavicular adenopathy are observed more frequently in cases
of leukemia and lymphoma than in cases of aplastic anemia).
• In any case of aplastic anemia, look for physical stigmata of inherited marrow-failure
syndromes, such as skin pigmentation, short stature, microcephaly, hypogonadism, mental
retardation, and skeletal anomalies. The oral pharynx, hands, and nail beds should be
carefully examined for clues of dyskeratosis congenita (see Image 1).

Causes

• Congenital or inherited causes of aplastic anemia (20%)

o Patients usually have dysmorphic features or physical stigmata. On occasion, marrow
failure may be the initial presenting feature.
o Fanconi anemia
o Dyskeratosis congenita
o Cartilage-hair hypoplasia
o Pearson syndrome
o Amegakaryocytic thrombocytopenia (thrombocytopenia-absent radius [TAR]
syndrome)
o Shwachman-Diamond syndrome
o Dubowitz syndrome
o Diamond-Blackfan syndrome
o Familial aplastic anemia
• Acquired causes of aplastic anemia (80%)
o Idiopathic factors
o Infectious causes, such as hepatitis viruses, Epstein-Barr virus (EBV), human
immunodeficiency virus (HIV), parvovirus, and mycobacteria
o Toxic exposure to radiation and chemicals, such as benzene
o Drugs and elements, such as chloramphenicol, phenylbutazone, and gold may cause
aplasia of the marrow. The immune mechanism does not account for the marrow
failure in idiosyncratic drug reactions. In such cases, direct toxicity may occur,
perhaps due to genetically determined differences in metabolic detoxification
pathways. For example, the null phenotype of certain glutathione transferases is
overrepresented among patients with aplastic anemia.
o PNH is caused by an acquired genetic defect limited to the stem-cell compartment
affecting the PIGA gene. Mutations in the PIGA gene render cells of hematopoietic
origin sensitive to increased complement lysis. Approximately 20% of patients with
aplastic anemia have evidence of PNH at presentation, as detected by means of flow
cytometry. Furthermore, patients whose disease responds after immunosuppressive
therapy frequently recover with clonal hematopiesis and PNH.
o Transfusional GVHD
o Orthotopic liver transplantation for fulminant hepatitis
o Pregnancy
o Eosinophilic fasciitis
Laboratory Studies

• Determination of complete blood cell (CBC) count and peripheral smears

o A paucity of platelets, red blood cells (RBCs), granulocytes, monocytes, and
reticulocytes is found in patients with aplastic anemia. Mild macrocytosis is
occasionally observed. The degree of cytopenia is useful in assessing the severity of
aplastic anemia. The corrected reticulocyte count is uniformly low in aplastic anemia.
o The peripheral blood smear is often helpful in distinguishing aplasia from infiltrative
and dysplastic causes. Teardrop poikilocytes and leukoerythroblastic changes
suggest an infiltrative process.
o Patients with MDS often have certain characteristic abnormalities such as
dyserythropoietic RBCs and neutrophils with hypogranulation, hypolobulation, or
apoptotic nuclei reaching to the edges of the cytoplasm. Monocytes are similarly
hypogranular, and their nuclei may contain nucleoli.
o A leukemic process may result in evidence of blasts (myeloblasts) on the peripheral
smear.
• Peripheral blood testing
o Hemoglobin electrophoresis and blood-group testing may show elevated levels fetal
hemoglobin and red cell I antigen, suggesting stress erythropoiesis. These findings
are observed in both aplastic anemia and MDS and are often proportional to the
macrocytosis.
o Ordering a biochemical profile is useful in evaluating the etiology and in the
differential diagnosis. The profile includes a Coombs test; an analysis of kidney
function; and measurement of transaminase, bilirubin, and lactic dehydrogenase
(LDH) levels.
o Serologic testing for hepatitis and other viral entities, such as EBV, CMV, and HIV,
may be useful.
o An autoimmune-disease evaluation for evidence of collagen-vascular disease may be
performed.
o The Ham test, or the sucrose hemolysis test, is frequently performed to diagnose
PNH. However, at present, the fluorescence-activated cell sorter (FACS) profile of
PIGA anchor proteins, such as CD55 and CD59, may be more accurate than the
Ham test for excluding PNH.
o Diepoxybutane incubation is performed to assess chromosomal breakage for Fanconi
anemia. This test is required even in the absence of phenotypic features of Fanconi
anemia, because 30% of patients may not have any clinical stigmata.
o Histocompatibility testing should be conducted early to identify potential related
donors, especially those for young patients. Because the extent of previous
transfusion significantly affects the outcomes of patients undergoing BMT for aplastic
anemia, the rapidity with which these data are obtained is crucial.

Imaging Studies

• Radiologic studies are generally not needed to establish a diagnosis of aplastic anemia.
• A skeletal survey is especially useful for the inherited marrow-failure syndromes, many of
which cause skeletal abnormalities.

Procedures

• Review of peripheral smears

• Bone marrow aspiration and biopsy
o Bone marrow biopsy is performed in addition to aspiration to assess cellularity both
qualitatively and quantitatively. In aplastic anemia, the specimens are hypocellular.
Aspiration samples alone may appear hypocellular because of technical reasons (eg,
dilution with peripheral blood), or they may appear hypercellular because of areas of
focal residual hematopoiesis.By comparison, core biopsy better reveals cellularity:
 The specimen is considered hypocellular if it is <30% cellular in individuals aged <60
years or if it is <20% in those aged >60 years. A relative or absolute increase in mast
cells may be observed around the hypoplastic spicules. A proportion of marrow
lymphocytes >70% is correlated with poor prognosis in aplastic anemia. Some
dyserythropoiesis with megaloblastosis may be observed in aplastic anemia.
o In MDS, the cellularity may be increased or decreased. Myelodysplastic features are
usually observed in hematopoietic precursors and progeny. Islands of immature cells
or abnormal localization of immature progenitors (ALIP) indicate MDS. These patients
may have megakaryocytic abnormalities (micromegakaryocytes, megakaryocytes
with dyskaryorrhexis), >5% ring sideroblasts (observed only on iron stains), and
granulocytic abnormalities (pseudo – Pelger-Huët cells, hypogranulation, excess of
blasts) On occasion, marrow fibrosis may be observed.
o Leukemia and metastatic cancers may be diagnosed with bone marrow examination.
o Chromosomal rearrangements are considered diagnostic of MDS, with trisomies of 8
and 21 and deletions of 5, 7, and 20 being the most common. However, the
conventional karyotype technique reveals abnormalities in only about 50% of patients
with MDS. In hypoplastic marrows, obtaining sufficient sample for karyotyping is often
difficult.
o The issue of malignant versus nonmalignant clonality in aplastic anemia can
sometimes be resolved by using fluorescent in situ hybridization (FISH) to visualize
chromosomal abnormalities in interphase cells.
o Bone marrow culture is useful in diagnosing mycobacterial and viral infections.
However, the yield is generally low.

Histologic Findings

Histologic findings of aplastic anemia include hypocellular bone marrow with fatty replacement and
relatively increased nonhematopoietic elements, such as plasma cells and mast cells. Perform careful
examination to exclude metastatic tumor foci on biopsy.
Staging

Staging of aplastic anemia is based on the criteria of the International Aplastic Anemia Study Group,
as follows20 :

• Blood
o Neutrophils – Less than 0.5 X 109/L
o Platelets – Less than 20 X 109/L
o Reticulocytes – Less than 1% corrected (percentage of actual hematocrit [Hct] to
normal Hct)
• Marrow
o Severe hypocellularity
o Moderate hypocellularity, with hematopoietic cells representing less than 30% of
residual cells
• Severe aplasia is defined as including any 2 or 3 peripheral blood criteria and either marrow
criterion.
• A further subclassification developed after the recognition that individuals with neutrophil
counts lower than 0.2 X 109/L had very SAA (VSAA). This group is less likely than others to
respond to immunosuppressive therapy.

Medical Care

• Transfusions
o Patients with aplastic anemia require transfusion support until the diagnosis is
established and until specific therapy can be instituted.
o For patients in whom BMT may be attempted, transfusions should be used judiciously
because minimally transfused subjects have achieved superior therapeutic outcomes.
 o Avoiding transfusions from family members is important because of possible
sensitization against non-HLA tissue antigens of the donors.
o In considering blood-bank support, attempt to minimize the risk of CMV infection. If
possible, the blood products should undergo leukopoor reduction to prevent
alloimmunization, and they should be irradiated to prevent third-party GVHD in BMT
candidates.
o Judicious use of blood products is essential, and transfusion in conditions that are not
life threatening should be performed in consultation with a physician who
is experienced in the management of aplastic anemia.
• Treatment of infections
o Infections are a major cause of mortality.
o Risk factors include prolonged neutropenia and the indwelling catheters used for
specific therapy. Fungal infections, especially those due to Aspergillus species pose
a major risk.
o Empirical antibiotic therapy should be broad based, with gram-negative and
staphylococcal coverage based on local microbial sensitivities. Especially consider
including anti-pseudomonal coverage at the start of treatment for patients with febrile
neutropenia, and consider early introduction of antifungal agents for those with
persistent fever.
o Cytokine support with granulocyte colony-stimulating factor (G-CSF) and granulocyte-
macrophage colony-stimulating factor (GM-CSF) may be considered in refractory
infections, although this therapy should be weighed against cost and efficacy.2,21,22
• BMT with an HLA-matched sibling donor
o HLA-matched sibling-donor BMT is the treatment of choice for a young patient with
SAA (controversial but generally accepted for those aged <60 y).
o One of the major problems of BMT in aplastic anemia is the high 10% rate of
rejection (range, 5-50%), and this is positively correlated with the number of
transfusions and duration of disease before undergoing transplantation.
o The conditioning regimen most often used includes a combination of antithymocyte
globulin (ATG), cyclosporin (CSA), and cyclophosphamide.19,23,24 The addition of ATG
and CSA to the conditioning regimen has resulted in reduction of graft rejection.8,21,22,25
When radiation was used as part of the conditioning regimen, the incidence of graft
rejection was <5%, but the incidence of chronic GVHD, interstitial pneumonitis, and
malignant disease was increased; no survival advantage resulted.
o Fludarabine- and cyclophosphamide-based reduced intensity conditioning (RIC)
regimens +/– ATG reduced rejection and improved outcome in Indian patients
undergoing allogeneic stem cell transplantation for SAA.26 When compared with 26
patients previously transplanted using cyclophosphamide/antilymphocyte globulin,
there was faster neutrophil engraftment (12 vs 16 days; P = 0.002) with significantly
lower rejection rates (2.9% vs 30.7%; P = 0.003) and a superior event-free (82.8% vs
38.4%; P = 0.001) and overall survival (82.8% vs 46.1%; P = 0.005).26
o GVHD is a complication of BMT. It is positively correlated with increasing age of the
patient. Grafts depleted of T cells reduce the risk of GVHD but increase the risk of
graft failure.
o The addition of CSA along with methotrexate has substantially reduced the incidence
of GVHD.25
• BMT with an unrelated donor
o BMT with an unrelated donor is associated with a high mortality rate.
o Unrelated-donor BMT is probably justified only if the donor is a full match and only if
immunosuppressive therapy or treatment as part of a clinical trial fails. Early referral
to a transplantation center at diagnosis is recommended in all young patients, even if
they lack a suitable related donor.9
o Both increased graft rejection and increased GVHD remain obstacles to success for
unrelated-donor BMT for patients with SAA.13 The probability of graft failure at 100
days after 1-antigen mismatched related donor was 21% 25% for >1-antigen
mismatched related donor, 15% for matched unrelated donor, 18% for mismatched
 unrelated donor transplants.9 Partial T-cell depletion may decrease the risk of severe
GVHD while still maintaining sufficient donor T lymphocytes to ensure engraftment.13
o In unrelated-donor transplantation, radiation along with cyclophosphamide may be
used to reduce graft rejection. Fludarabine-based conditioning regimens have been
tried,14 along with ATG and cyclophosphamide.
o Unrelated-donor BMT using high resolution allelic matching has improved outcome
especially in younger patients.

• Immunosuppressive therapy
o Immune suppression is especially useful if a matched sibling donor for BMT is not
available or if the patient is older than 60 years.
o Options include combination therapy, including ATG, CSA, and methylprednisolone,
with or without cytokine support. ATG and CSA alone may also produce a response
in aplastic anemia, but the combination improves the likelihood of a response.
o In 1 study, response rates to CSA alone were 45% overall, 16% for VSSA, 47% for
SAA, and 85% for moderate aplastic anemia.23 Therefore, the only predictor of
response to CSA was an absolute neutrophil count (ANC) of <200/mm3. Adding G-
CSF to ATG and CSA in patients with an ANC of >200/mm3 does not produce any
additional advantage in reducing the infection rate or in increasing survival or
therapeutic responses.
o The response in aplastic anemia, unlike other autoimmune diseases, is slow. At least
4-12 weeks is usually needed to observe early improvement, and the patient
continues to improve only slowly thereafter. About 50% patients respond by 3 months
after ATG administration, and about 75% respond by 6 months. Most patients
improve and become transfusion independent, but many still have evidence of a
hypoproliferative bone marrow.
o Although the initial response rate is good, relapses are common, and continued
immune suppression is often needed. Approximately one third of patients have a
relapse, most of whom have a relapse at the time of CSA taper. About one third of
responders are CSA dependent. Of patients whose conditions have no response or
who relapse, 40-50% respond to a second course of immunosuppressive therapy.
o In rare cases, full hematologic recovery is observed, but most patients improve to a
functional hematologic recovery that obviates further transfusion support.
Furthermore, the risk of some form of clonal disease other than PNH is 15-30% and
may be due to the inability of these therapies to completely correct bone marrow
function, due to a missed diagnosis of MDS, or due to the fact that the stem cells
under proliferative stress may be more prone than other cells to mutation.
o Preliminary data suggested that high-dose cyclophosphamide may result in durable
remissions in some patients with aplastic anemia. However, some of these patients
develop PNH and cytogenetic abnormalities on follow-up. At present, the use of high-
dose cyclophosphamide should be limited to clinical trials.

Surgical Care

A central venous catheter placement is required before the administration of immunosuppressive

therapy or BMT.
Diet

The diet for the patient with aplastic anemia who has neutropenia or who is receiving
immunosuppressive therapy should be tailored carefully to exclude raw meats, dairy products, or fruits
and vegetables that are likely to be colonized with bacteria, fungus, or molds. Furthermore, a salt-
limited diet is recommended during therapy with steroids or CSA.
Activity

• The patient should avoid any activity that increases the risk of trauma during periods of
thrombocytopenia.
• The risk of community-acquired infections increases during periods of neutropenia.
Medication

The goals of pharmacotherapy in cases of aplastic anemia are to reduce morbidity, prevent
complications, and eradicate malignancy.

Immunosuppressive Agents

The merits of additional immunosuppression versus the increased risk and cost should be considered.
Data from a randomized prospective study indicated that an increased proportion of patients
responded to the addition of CSA to ATG, but this did not translate into a long-term survival
advantage.
For patients who cannot tolerate equine-based products, use of the commercially available rabbit-
based ATG product (Thymoglobulin) may be considered. This product is currently approved in the
United States and has been used for the treatment of aplastic anemia in Europe (although note the
different dose schedule).

Cyclosporine (Sandimmune, Neoral)

Cyclic polypeptide that suppresses some humoral immunity and, to a greater extent, cell-mediated
immune reactions (eg, delayed hypersensitivity, allograft rejection, experimental allergic
encephalomyelitis, and graft vs host disease) for a variety of organs.

For children and adults, base the dosing on the ideal body weight. Frequent monitoring of drug levels
is needed. To convert to the PO dose, use a IV-to-PO correction factor of 1:4. Dosage and duration of
therapy may vary with different protocols.
Adult

1.5-2 mg/kg IV q12h, adjust to trough level of 500-800 ng/mL in mo 1 or so; then adjust to trough level
of 200 ng/mL
Pediatric

Administer as in adults.

Methylprednisolone (Medrol, Solu-Medrol)

Steroids ameliorate the delayed effects of anaphylactoid reactions and may limit biphasic anaphylaxis.
In severe serum sickness (mediated by immune complexes), parenteral steroids may reduce the
inflammatory effects. Hence, used with ATG to decrease the adverse effects (eg, allergic reactions,
serum sickness). Also an additional immunosuppressive. High doses or long duration may be needed
if serum sickness occurs with ATG. The doses and duration may vary with different protocols.

•
Adult

5 mg/kg IV on days 1-8; then tapered by using PO 1 mg/kg on days 9-14; further tapering over days
15-29; stop after 1 mo except with evidence of serum sickness
Pediatric

Administer as in adults.

Lymphocyte immune globulin, equine (Atgam)

Inhibits cell-mediated immune response by altering T-cell function or eliminating antigen-reactive cells.
There is little prospective randomized data to suggest a single schedule superior, but experience
suggests that a short infusion is best tolerated.
Adult

100-200 mg/kg IV total dose over variable number of days based on different protocols
Pediatric

Administer as in adults.
Cyclophosphamide (Cytoxan)

Chemically related to nitrogen mustards. As an alkylating agent, the mechanism of action of the active
metabolites may involve cross-linking of DNA, which may interfere with the growth of normal and
neoplastic cells. Monitor carefully; used only on an investigational basis.
45 mg/kg/d IV for 4 d
Pediatric

Administer as in adults

Lymphocyte immune globulin, rabbit (Thymoglobulin)

May modify T-cell function and possibly eliminate antigen-reactive T lymphocytes in peripheral blood.
The dose and duration of therapy vary with the investigational protocols.
Adult

1.5 mg/kg IV qd for 7-14 d; up to 3.5 mg/kg for 5 d also used

Pediatric

Not established
Several preliminary studies have demonstrated that the addition of cytokines (eg, G-CSF, GM-CSF)
may hasten the neutrophil recovery and that these agents may improve the response rate and
survival, although long-term use may increase the risk of clonal evolution.

Sargramostim (Leukine, Prokine)

Recombinant human GM-CSF. Can activate mature granulocytes and macrophages. The dose and
frequency of administration vary with the investigational protocol.

Adult

250 mcg/m2 IV/SC with twice weekly monitoring of CBC count

Pediatric

Not established; 5 mcg/kg/d SC used in some studies

Filgrastim (Neupogen)

G-CSF that activates and stimulates the production, maturation, migration, and cytotoxicity of
neutrophils.
Adult

5 mcg/kg/d SC until ANC 5000/mm3

Pediatric

5-10 mcg/kg/d SC
Antineoplastic Agent, Antimetabolite (purine)

Antimetabolites are antineoplastic agent that inhibit cell growth and proliferation.

Fludarabine (Fludara)

Contains fludarabine phosphate, a fluorinated nucleotide analogue of the antiviral agent vidarabine, 9-
b-D-arabinofuranosyladenine (ara-A) that enters the cell and is phosphorylated to form active
metabolite 2-fluoro-ara-ATP, which inhibits DNA synthesis. Inhibits DNA polymerase, DNA primase,
DNA ligase, and ribonucleotide reductase. This inhibits RNA function, RNA processing, and mRNA
translation. Also activates apoptosis.
Adult

30 mg/m2/dose for 4-6 d as IV infusion over 30 min-2 h

Pediatric
Administer as in adults

Complications

• Complications of aplastic anemia

o Infections
o Bleeding
• Complications of BMT
o GVHD
o Graft failure

Prognosis

• The outcome of patients with aplastic anemia has substantially improved because of improved
supportive care. The natural history of aplastic anemia suggests that as many as one fifth of
patients may spontaneously recover with supportive care; however, observational and/or
supportive care therapy alone is rarely indicated.
• The estimated 5-year survival rate for the typical patient receiving immunosuppression is
75%. The rate for those receiving a BMT from a matched sibling donor is greater than 90%.
However, in case of immunosuppression, relapse and late clonal disease are risks.

Patient Education

• Patients should maintain hygiene to reduce the risks of infection.

• Clinicians must stress the need for compliance with therapy.

Miscellaneous

Medicolegal Pitfalls

• Failure to correctly diagnose aplastic anemia and initiate appropriate treatment is a pitfall.
• Aplastic anemia has a >70% mortality rate with supportive care alone. It is a hematologic
emergency, and care should be instituted promptly.