aplastic anemia _ the symptoms, cause and treatment _ majelis ilm

8/19/2019 APLASTIC ANEMIA _ the Symptoms, Cause and Treatment _ Majelis Ilm

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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.

For excellent patient education resources, visit eMedicine‘s Blood and Lymphatic System Center. Also, see

eMedicine’s patient education article 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

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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 suppress 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

ymphocytes 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.

nternational

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

ncidence 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

iving in the United States.

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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.6,17,18,19,20

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 childhoodbecause 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

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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.

n 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 clinicalhepatitis.21,22

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).

n 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. Ora

eukoplakia is shown in the image below.

Oral leukoplakia in dyskeratosis congenita

Causes

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

Patients usually have dysmorphic features or physical stigmata. On occasion, marrow failure may be the

initial presenting feature.


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Fanconi anemia

Dyskeratosis congenita

Cartilage‑hair hypoplasia

Pearson syndrome

Amegakaryocytic thrombocytopenia (thrombocytopenia‑absent radius [TAR] syndrome)

Shwachman‑Diamond syndrome

Dubowitz syndrome

Diamond‑Blackfan syndrome

Familial aplastic anemia

Acquired causes of aplastic anemia (80%):

Idiopathic factors

Infectious causes, such as hepatitis viruses, Epstein‑Barr virus (EBV), human immunodeficiency virus

(HIV), parvovirus, and mycobacteria

Toxic exposure to radiation and chemicals, such as benzene

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.

PNH is caused by an acquired genetic defect limited to the stem‑cell compartment affecting

the PIGAgene. 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.

Transfusional GVHD

Orthotopic liver transplantation for fulminant hepatitis

Pregnancy

Eosinophilic fasciitis

Differential Diagnoses

Acute Lymphoblastic Leukemia Myelodysplastic Syndrome

Acute Myelogenous Leukemia Myelophthisic Anemia

Agnogenic Myeloid Metaplasia With Myelofibrosis Osteopetrosis

Human Herpesvirus Type 6 Systemic Lupus Erythematosus

Lymphoma, Non‑Hodgkin

Megaloblastic Anemia


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Multiple Myeloma

Other Problems to Be Considered

Congestive splenomegaly, resulting in hypersplenism Infectious etiology, such as infection with HIV,

mycobacteria,cytomegalovirus (CMV), or EBV Sepsis

Workup Laboratory Studies

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

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.

The peripheral blood smear is often helpful in distinguishing aplasia from infiltrative and dysplastic causes.

Teardrop poikilocytes and leukoerythroblastic changes suggest an infiltrative process.

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.

A leukemic process may result in evidence of blasts (myeloblasts) on the peripheral smear.

Peripheral blood testing

Hemoglobin electrophoresis and blood‑group testing may show elevated levels fetal hemoglobin and red cell

antigen, suggesting stress erythropoiesis. These findings are observed in both aplastic anemia and MDS and

are often proportional to the macrocytosis.

Ordering a biochemical profile is useful in evaluating the etiology and in the differential diagnosis. The profile

ncludes a Coombs test; an analysis of kidney function; and measurement of transaminase, bilirubin, and

actic dehydrogenase (LDH) levels.

Serologic testing for hepatitis and other viral entities, such as EBV, CMV, and HIV, may be useful.

An autoimmune‑disease evaluation for evidence of collagen‑vascular disease may be performed.

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


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more accurate than the Ham test for excluding PNH.

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.

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

Procedures include review of peripheral smears and bone marrow aspiration and biopsy, as described below.

Bone marrow aspiration and biopsy

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 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.

n MDS, the cellularity may be increased or decreased. Myelodysplastic features are usually observed in

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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.

Leukemia and metastatic cancers may be diagnosed with bone marrow examination.

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

n only about 50% of patients with MDS. In hypoplastic marrows, obtaining sufficient sample for karyotyping

s often difficult.

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.

Bone marrow culture is useful in diagnosing mycobacterial and viral infections. However, the yield is generally

ow.

Histologic Findings

Histologic findings of aplastic anemia include hypocellular bone marrow with fatty replacement and relatively

ncreased 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

follows :

Blood

Neutrophils – Less than 0.5 X 109/L

Platelets – Less than 20 X 109/L

Reticulocytes – Less than 1% corrected (percentage of actual hematocrit [Hct] to normal Hct)

MarrowSevere hypocellularity

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.


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Treatment Medical Care

Transfusion

Patients with aplastic anemia require transfusion support until the diagnosis is established and until specific

therapy can be instituted.

For patients in whom BMT may be attempted, transfusions should be used judiciously because minimally

transfused subjects have achieved superior therapeutic outcomes.

Avoiding transfusions from family members is important because of possible sensitization against non‑HLA

tissue antigens of the donors.

n 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.

udicious 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

nfections are a major cause of mortality.

Risk factors include prolonged neutropenia and the indwelling catheters used for specific therapy. Fungal

nfections, especially those due to Aspergillus species pose a major risk.

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.

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.2,26,27,28

BMT with an HLA‑matched sibling donor

HLA‑matched sibling‑donor BMT is the treatment of choice for a young patient with SAA (controversial but

generally accepted for those aged

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.

The conditioning regimen most often used includes a combination of antithymocyte globulin (ATG),


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cyclosporin (CSA), and cyclophosphamide.19,29,30,31,32 The addition of ATG and CSA to the conditioning

regimen has resulted in reduction of graft rejection.8,26,27,33 When radiation was used as part of the

conditioning regimen, the incidence of graft rejection was

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.34 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).34

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.

The addition of CSA along with methotrexate has substantially reduced the incidence of GVHD.33

BMT with an unrelated donor

BMT with an unrelated donor is associated with a high mortality rate.

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

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

n 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.

Unrelated‑donor BMT using high resolution allelic matching has improved outcome especially in younger

patients.

A study by Maury et al indicated the increased survival of patients after unrelated‑done stem cell

transplantation for SAA has improved significantly in the past 15 years mainly due to better HLA matching.

Maury et al found that results for young patients who are fully HLA‑matched at the allelic level with their

donor are comparable to those observed after stem cell transplantation from a related donor.35 An earlier

apanese study appeared to have reached a similar conclusion.36

A study by Chan et al suggests that unrelated‑donor BMT is a feasible treatment strategy for children with

refractory SAA who lack a well‑matched adult donor.12 The investigators evaluated 9 children with refractory

SAA (all had had at least 1 unsuccessful course of immunosuppression) who underwent such a transfusion

with increasingly immunosuppressive preparative regimens.


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Donor/recipient HLA matching was 6 of 6 (n = 1), 5 of 6 (n = 2), and 4 of 6 (n = 6). The median nucleated

cell dose infused was 5.7 x 107 cells/kg (range 3.5‑20 x 107 cells/kg). Six patients were engrafted after the

first unrelated‑donor BMT, and 2 of the 3 patients without hematopoietic reconstitution were engrafted after

a second transfusion. All children who received ≥ 120 mg/kg of cyclophosphamide in the preparative

regimen were engrafted. The median time to myeloid engraftment was 25 (17‑59 days) days.12

Two patients developed acute GVHD, and 5 developed chronic GVHD. Five patients developed EBV viremia

post transplant (lymphoproliferative disorder in 3 patients). At a median follow‑up of 34 months, 7 patients

were alive and transfusion independent.12

Immunosuppressive therapy

mmune suppression is especially useful if a matched sibling donor for BMT is not available or if the patient is

older than 60 years.

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.

n one study, response rates to CSA alone were 45% overall, 16% for VSSA, 47% for SAA, and 85% for moderate

aplastic anemia.29 Therefore, the only predictor of response to CSA was an absolute neutrophil count (ANC)

of 200/mm3 does not produce any additional advantage in reducing the infection rate or in increasing

survival or therapeutic responses.

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.

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.

n 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.

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.


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Surgical Care

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

BMT.

Consultations

Consult a hematologist and/or BMT specialist.

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

ikely 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.

mmunosuppressive 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)


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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.

Dosing

Interactions

Contraindications

Precautions

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.

Dosing

Interactions

Contraindications

Precautions

Adult5 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



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Lymphocyte immune globulin, equine (Atgam)

nhibits 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.

Dosing

Interactions

Contraindications

Precautions

Adult

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

Pediatric


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.

Dosing

Interactions

Contraindications

Precautions

Adult

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.

Dosing

Interactions


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Contraindications

Precautions

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

Cytokines

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

ong‑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.

Dosing

Interactions

Contraindications

Precautions

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.

Dosing

Interactions

Contraindications

Precautions

Adult


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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, andribonucleotide reductase. This inhibits RNA function, RNA processing, and mRNA translation. Also activates

apoptosis.

Dosing

Interactions

Contraindications

Precautions

Adult

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

Pediatric

Administer as in adults

Follow‑upFurther Inpatient Care

npatient care for patients with aplastic anemia may be needed during periods of infection and for specific

therapies, such as ATG or BMT.

Further Outpatient Care

Frequent outpatient follow‑up of patients with aplastic anemia is needed to monitor blood counts and

adverse effects of various drugs.


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Transfusions of packed RBCs and platelets are administered on an outpatient basis.

Inpatient & Outpatient Medications

The specific medications administered depend on the choice of therapy and whether it is supportive care

only, immunosuppressive therapy, or BMT.

Transfer

Patients with aplastic anemia should be treated by physicians who are experts in the care of

mmunocompromised patients and in consultation with a BMT physician for patients younger than 65 years.

Complications

Complications of aplastic anemia include infections and bleeding.

Complications of BMT include GVHD and 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

mmunosuppression, relapse and late clonal disease are risks.

n a single institution analysis of 183 patients who received immunosuppressive treatments for severe

aplastic anemia, the telomere length of peripheral blood leukocytes was unrelated to treatment response. In a

multivariate analysis, however, telomere length was associated with risk of relapse, clonal evolution, and

overall survival. Additional studies are needed to validate these findings and to determine how this

nformation might be incorporated into treatmentalgorithms.37

Patient EducationPatients should maintain hygiene to reduce the risks of infection.

Clinicians must stress the need for compliance with therapy.

Miscellaneous


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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.

aplastic anemia _ the symptoms, cause and treatment _ majelis ilm

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