AUTHOR INFORMATION

Section 1 of 11

Authored by Sameer Bakhshi, MD, Fellow, Department of Pediatric Hematology/Oncology, Children's Hospital of Michigan, Wayne State University

Coauthored by Roy Baynes, MB, BCh, PhD, FACP, Charles Martin Professor of Cancer Research, Department of Internal Medicine, Division of Hematology and Oncology, Karmanos Cancer Institute, Wayne State University; Esteban Abella, MD, Medical Director of Inpatient Care Unit Pediatric Hematology Oncology, Associate Professor, Departments of Internal Medicine and Pediatrics, Childrens Hospital of Michigan, Wayne State University

Edited by David Aboulafia, MD, Medical Director, Bailey-Boushay House; Clinical Professor, Department of Medicine, Division of Hematology, University of Washington; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Troy H Guthrie, Jr, MD, Chief, Professor of Medicine, Division of Hematology/Oncology, University of Florida Health Science Center; Rajalaxmi McKenna, MD, FACP, Director, Hemophilia Center, Special Hematology and Hemostasis Laboratory; Clinical Professor, Department of Medicine, Cardeza Foundation for Hematological Research, Thomas Jefferson University and Hospital; and Emmanuel C Besa, MD, Professor, Department of Internal Medicine, Division of Hematology and Oncology, Medical College of Pennsylvania Hahnemann University

 

Author's Email:	Sameer Bakhshi, MD
Editor's Email:	David Aboulafia, MD

eMedicine Journal, June 19 2001, Volume 2, Number 6

INTRODUCTION

Section 2 of 11

Background: Aplastic anemia is a marrow failure syndrome characterized by peripheral pancytopenia and marrow hypoplasia. Dr 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 this disorder was termed aplastic anemia by Chauffard.

Pathophysiology: The theoretical basis for marrow failure includes primary defects in, or damage to, the stem cell or the marrow microenvironment. 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.

Morphologically, 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 significantly reduced. In vitro colony culture assays suggest profound functional loss of the hematopoietic progenitors, so much so that they are unresponsive even to very 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, the stromal cell function is normal, including growth factor production. Adequate stromal function is implicit in the success of marrow transplantation in aplastic anemia because frequently the stromal elements remain of host origin.

The role of an immune dysfunction was suggested in 1970, when autologous recovery was documented in a patient with aplastic anemia who had failed to engraft after marrow transplantation; Mathe proposed that the immunosuppressive regimen used for conditioning promoted the return of normal marrow function. Subsequently, numerous studies have shown that in approximately 70% of patients with acquired aplastic anemia, immunosuppressive therapy improves marrow function. Immunity is regulated genetically (by immune response genes) and also influenced by environment (eg, nutrition, aging, previous exposure). Although the inciting antigens that breach immune tolerance with subsequent autoimmunity are unknown, human leukocyte antigen (HLA)-DR2 is overrepresented among European and American patients with aplastic anemia.

Suppression of hematopoiesis likely is mediated by an expanded population of cytotoxic T lymphocytes: cluster of differentiation 8, HLA-DR+ (CTLs: CD8, 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 are capable of suppressing progenitor cell growth. These cytokines suppress hematopoiesis by affecting the mitotic cycle and cell killing through induction Fas-mediated apoptosis. It also has been shown that these cytokines induce nitric oxide synthase and nitric oxide production by marrow cells, which contributes to immune-mediated cytotoxicity and elimination of hematopoietic cells.

Frequency:

• In the US: No accurate prospective data are available regarding the incidence of aplastic anemia in the US. Several retrospective studies suggest that the incidence ranges from 0.6-6.1 per million, largely based on data from retrospective reviews of death registries.

• Internationally: The annual incidence of aplastic anemia in Europe as detailed in large, formal epidemiological studies is similar to the US data at 2 per million. Aplastic anemia is thought to be more common in the Orient than in the West. The incidence was accurately determined at 4 per million in Bangkok but may be closer to 6 per million in the rural areas of Thailand and as high a 14 per million in Japan, based on prospective studies. This increased incidence may be related to environmental factors, such as increased exposure to toxic chemicals, rather than genetic factors since this increase is not seen in people of Oriental ancestry presently living in US.

Mortality/Morbidity: The major causes of morbidity and mortality from aplastic anemia include infection and bleeding. Patients who undergo bone marrow transplantation have additional issues related to conditioning regimen toxicity and graft-versus-host disease. With immunosuppression, approximately one third of patients do not respond, and for the responders risks exist of relapse and late onset clonal disease such as paroxysmal nocturnal hemoglobinuria (PNH), myelodysplastic syndrome (MDS), and leukemia.

Race: No racial predisposition in US; however, increased prevalence in the Far East

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

Age: Aplastic anemia occurs in all age groups.

• A small peak in childhood is seen due to the inclusion of inherited marrow failure syndromes.

• The peak incidence of aplastic anemia is seen in the 20-25 years age group, and a subsequent peak is seen after the age of 60 years. The latter peak may be due to inclusion of MDS, which are stem cell failure syndromes unrelated to aplastic anemia. These must be considered in the differential diagnosis of any marrow failure syndrome.

CLINICAL

Section 3 of 11

History: The clinical presentation of aplastic anemia includes symptoms related to the decrease in bone marrow production of hematopoietic cells. The onset is insidious, with the initial symptom relating to anemia or bleeding, but fever or infections often are noted at presentation.

• Anemia may manifest as pallor, headache, palpitations, dyspnea, fatigue, or foot swelling.

• Thrombocytopenia may present as mucosal and gingival bleeding or petechial rashes.

• Neutropenia may manifest as overt infections, recurrent infections, or mouth and pharyngeal ulcerations.

• Even though the search for an etiologic agent often is unproductive, an appropriately detailed work history with emphasis on solvent and radiation exposure, family, environmental, travel, and infectious disease history should be obtained.

• Significantly, in the absence of obvious phenotypic features, the presentation of an inherited marrow failure syndrome is subtle, and it may first be suggested by a thorough family history.

• With regard to environmental agents, it is important to remember that much variation is seen in the time course of the occurrence of aplastic anemia and the exposure to the offending agent, and only rarely is an environmental etiology identified.

Physical: The physical examination may show signs of anemia, such as pallor and tachycardia, and of thrombocytopenia, such as petechiae, purpura, or ecchymoses. Overt signs of infection usually are 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.

• In any case of aplastic anemia, one should look for physical stigmata of inherited marrow failure syndromes such as skin pigmentation, short stature, microcephaly, hypogonadism, mental retardation, and skeletal anomalies. A careful examination of the oral pharynx, hands, and nailbeds should be preformed looking for clues of dyskeratosis congenita.

Causes:

• Congenital/inherited (20%)

• Patients usually have dysmorphic features or physical stigmata. Occasionally, marrow failure may be the initial presenting feature.

   

• Fanconi anemia

• Dyskeratosis congenita

• Cartilage hair hypoplasia

• Pearson syndrome

• Amegakaryocytic thrombocytopenia (TAR syndrome)

• Shwachman-Diamond syndrome

• Dubowitz syndrome

• Diamond-Blackfan syndrome

• Familial aplastic anemia

• Acquired (80%)

• Idiopathic

• Infectious causes such as hepatitis viruses, Ebstein-Barr virus (EBV), HIV, parvovirus, and mycobacterial infections

• Toxic exposure to radiation and chemicals such as benzene

• Drugs such as chloramphenicol, phenylbutazone, and gold may cause aplasia of the marrow. The immune mechanism does not explain 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.

• Paroxysmal nocturnal hemoglobinuria (PNH) is caused by an acquired genetic defect limited to the stem cell compartment affecting the PIGA gene. The PIGA gene mutations 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 flow cytometry. Furthermore, patients who respond following immunosuppressive therapy frequently recover with clonal hematopiesis and PNH.

• Transfusional graft-versus-host disease

• Orthotopic liver transplantation for fulminant hepatitis

• Pregnancy

• Eosinophilic fascitis

DIFFERENTIALS

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Acute Lymphoblastic Leukemia
Acute Myelogenous Leukemia
Agnogenic Myeloid Metaplasia with Myelofibrosis
Human Herpesvirus Type 6 (HHV-6)
Lymphoma, Non-Hodgkin
Megaloblastic Anemia
Myelodysplastic Syndrome
Myelophthisic Anemia
Osteopetrosis

Other Problems to be Considered:

Multiple myeloma
Congestive splenomegaly resulting in hypersplenism
Sepsis
Disseminated lupus erythematosus
Infectious etiology such as HIV, mycobacterial infections, cytomegalovirus (CMV), EBV

WORKUP

Section 5 of 11

Lab Studies:

• CBC and peripheral smear

• A paucity of platelets, red blood cells, granulocytes, monocytes, and reticulocytes is found. Mild macrocytosis sometimes is encountered. 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 often is helpful in resolving aplasia from infiltrative and dysplastic causes. The presence of teardrop poikilocytes and leucoerythroblastic changes is suggestive of an infiltrative process.

• Patients with MDS often show certain characteristic abnormalities: dyserythropoietic red blood cells; 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 show evidence of blasts on the peripheral smear.

• Bone marrow aspiration and biopsy

• A bone marrow biopsy is performed in addition to the aspiration so that the cellularity may be assessed both qualitatively and quantitatively. In aplastic anemia, these specimens are hypocellular. Aspirations alone may appear hypocellular owing to technical reasons (eg, dilution with peripheral blood), or they may look hypercellular because of areas of focal residual hematopoiesis. A core biopsy gives a better idea of cellularity; the specimen is considered hypocellular if it is less than 30% cellular in individuals younger than 60 years or less than 20% in those older than 60 years. A relative or absolute increase in mast cells may be observed around the hypoplastic spicules. A proportion of marrow lymphocytes greater than 70% has been correlated with poor prognosis in aplastic anemia. Some dyserythropoiesis with megaloblastosis may be seen in aplastic anemia.

• In MDS, the cellularity may be increased or decreased. Myelodysplastic features usually are observed in hematopoietic precursors and progeny. Islands of immature cells or abnormal localization of immature progenitors (ALIPS) are indicative of MDS. These patients may have megakaryocytic abnormalities (micromegakaryocytes, megakaryocytes with dyskaryorrhexis); greater than 5% ring sideroblasts (seen only on iron stains); granulocytic abnormalities (pseudo-Pelger-Huët cells, hypogranulation, excess of blasts); occasionally, marrow fibrosis may be observed.

• Patients with leukemia and metastatic cancers also 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 most common. However, the conventional karyotype technique reveals abnormalities in only about 50% of patients with MDS. In hypoplastic marrows, it often is difficult to obtain sufficient sample for karyotyping.

• The issue of malignant versus nonmalignant clonality in aplastic anemia can at times be resolved 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 generally is low.

• Peripheral blood

• Hemoglobin electrophoresis and blood group testing may show elevated fetal hemoglobin and red cell I antigen suggesting stress erythropoiesis, which is seen in both aplastic anemia and MDS and often is proportional to the macrocytosis.

• Biochemical profile including evaluation of transaminases, bilirubin, lactic dehydrogenase, Coombs test, and kidney function is useful in evaluating etiology and differential diagnosis.

• Serologic testing for hepatitis and other viral entities such as EBV, CMV, and HIV

• Autoimmune disease evaluation for evidence of collagen-vascular disease

• Ham test or sucrose hemolysis test frequently are performed, but currently fluorescent activated cell sorter profile of PIGA gene anchor proteins such as CD55 and CD59 may be more accurate 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 such patients may not have any clinical stigmata.

• Histocompatibility testing should be conducted early to establish potential related donors, especially in younger patients. Because the outcome of patients undergoing allogenic bone marrow transplantation for aplastic anemia is significantly affected by the extent of prior transfusion, the rapidity with which these data are obtained is crucial.

Imaging Studies:

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

Procedures:

• Review of peripheral smear

• Bone marrow aspiration and biopsy

Staging: Based on International Aplastic Anemia Study Group (Camitta et al)

• Blood

• Neutrophils - Less than 0.5x10'9/L

• Platelets - Less than 20x10'9/L

• Reticulocytes - Less than 1% (corrected) (percentage of actual Hct/normal Hct)

• Marrow

• Severe hypocellularity

• Moderate hypocellularity with hematopoietic cells representing less than 30% of residual cells

• Severe aplasia is defined by any 2 or 3 peripheral blood criteria and either marrow criterion.

• A further subclassification followed the recognition that individuals with neutrophils below 0.2x10'9/L constituted a very severe aplastic anemia (VSAA) group. This group is less likely to respond to immunosuppressive therapy.

TREATMENT

Section 6 of 11

Medical Care:

• Transfusions

  Patients with aplastic anemia require transfusion support until the diagnosis is established and specific therapy can be instituted. For patients in whom marrow transplantation may be attempted, transfusions should be used judiciously because minimally transfused subjects have achieved superior therapeutic outcomes. It is important to avoid transfusions from family members because of possible sensitization against non-HLA tissue antigens of the donors. In considering blood bank support, attempt to minimize the risk of cytomegalovirus infection. If possible, the blood products should undergo leuko-poor reduction to prevent alloimmunization and be irradiated for prevention of third-party graft-versus-host disease in bone marrow transplant candidates. Judicious use of blood products is essential, and transfusion in conditions that are not life threatening should be done in consultation with a physician experienced in the management of aplastic anemia.

• Treatment of infections

  Infections are a major cause of mortality in these patients. The risk factors include prolonged neutropenia and the indwelling catheters used for specific therapy. Fungal infections, especially Aspergillus, pose a major risk. Empirical antibiotic therapy should be broad based with gram-negative and staphylococcal coverage, based on local microbial sensitivities. Special consideration should be given to include antipseudomonal coverage at initiation of treatment for patients with febrile neutropenia and 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, though weighted against cost and efficacy.

• Bone marrow transplantation

  HLA-matched sibling donor bone marrow transplantation (BMT) is the treatment of choice for a patient with severe aplastic anemia in young patients (controversial but generally accepted for age <60 years). The conditioning regimen most often used includes a combination of antithymocyte globulin (ATG), cyclosporine (CSA) and cyclophosphamide. The addition of ATG and CSA to the conditioning regimen has resulted in reduction of graft rejection. When radiation was used as part of the conditioning regimen, a higher incidence of chronic graft-versus-host disease and malignant disease was found.

  Unrelated donor BMT probably can only be justified if the donor is a full match and has failed immunosuppressive therapy or as part of a clinical trial. Early referral to a transplant center at diagnosis is recommended in all younger patients, even if they lack a suitable related donor.

• Immunosuppressive therapy

  Immune suppression as a treatment for aplastic anemia is especially useful if a matched sibling donor for BMT is not available or if the patient is older than 60 years. The various options include combination therapy including ATG, CSA, and methylprednisolone, with or without cytokine support.

  The response, unlike other autoimmune diseases, is slow and usually takes at least 4-12 weeks to show early improvement, and continues to improve only slowly thereafter. Most patients improve and become transfusion-independent, but many still have evidence of a hypoproliferative bone marrow. Even though the initial response rate is good, relapses are common and often continued immune suppression is needed. Rarely is a full hematological recovery seen, but most patients improve to a functional hematological recovery that obviates further transfusion support. Further, a 15-30% risk exists of developing some form of clonal disease other than PNH, which may be due to the inability of these therapies to completely correct bone marrow function, the missed diagnosis of MDS, or the fact that the stem cells under proliferative stress may be more prone to mutation.

  Preliminary data suggested that high-dose cyclophosphamide may result in durable remissions in some patients with aplastic anemia, but a recent report suggests that rates of fungal infections may practically limit this approach, and its use at present should be limited to clinical trials.

Surgical Care: A central venous catheter is required prior to immunosuppressive therapy or BMT.

Consultations: Hematologist and/or bone marrow transplant specialist

Diet: The diet for the patient with aplastic anemia who is neutropenic or on immunosuppressive therapy should be carefully tailored to exclude raw meats, dairy products or fruits and vegetables that are likely to be colonized with bacteria, fungus, or molds. Further, a diet limiting salt is recommended during therapy with steroids or cyclosporine.

Activity:

• The patient should avoid the following:

• Any activity that increases the risk of trauma during periods of thrombocytopenia

• Risk of community-acquired infections during periods of neutropenia

MEDICATION

Section 7 of 11

The goals of pharmacotherapy are to reduce morbidity, prevent complications, and eradicate the malignancy.

Drug Category: Immunosuppressive agents - Consideration should be given to the merits of additional immunosuppression versus the increased risk and cost. A randomized prospective study indicated that a higher proportion of patients responded to the addition of cyclosporin to ATG, but this did not translate into long-term survival advantage.
Patients who are intolerant of equine-based products may be considered for the commercially available rabbit-based ATG product (Thymoglobulin) that was approved recently in the US and has been used for the treatment of aplastic anemia in Europe (note very different dose schedule).

Drug Name	Cyclosporine (Sandimmune, Neoral)- Cyclic polypeptide that suppresses some humoral immunity and, to a greater extent, cell-mediated immune reactions such as delayed hypersensitivity, allograft rejection, experimental allergic encephalomyelitis, and graft-vs-host disease for a variety of organs. For children and adults, base dosing on ideal body weight. Needs frequent drug level monitoring. To convert to PO dose, use a correction factor of 1:4 (IV:PO). Dosage and duration of therapy may vary with different protocols.
Adult Dose	1.5-2 mg/kg IV q12h; adjust to trough level of 500-800 ng/mL in initial 1 mo or so, then later adjust to trough level of 200 ng/mL
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; uncontrolled hypertension or malignancies; do not administer concomitantly with PUVA or UVB radiation in psoriasis since it may increase risk of cancer
Interactions	Carbamazepine, phenytoin, isoniazid, rifampin, and phenobarbital may decrease cyclosporine concentrations; azithromycin, itraconazole, nicardipine, ketoconazole, fluconazole, erythromycin, verapamil, grapefruit juice, diltiazem, aminoglycosides, acyclovir, amphotericin B, and clarithromycin may increase cyclosporine toxicity; acute renal failure, rhabdomyolysis, myositis, and myalgias increase when taken concurrently with lovastatin
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Evaluate renal and liver functions often by measuring BUN, serum creatinine, serum bilirubin and liver enzymes; may increase risk of infection and lymphoma; reserve IV use only for those who cannot take PO

Drug Name	Methylprednisolone (Medrol, Solu-Medrol)- Steroids ameliorate delayed effects of anaphylactoid reactions and may limit biphasic anaphylaxis. In severe cases of serum sickness, parenteral steroids may be beneficial to reduce inflammatory effects of this immune-complex mediated disease. Hence, used in combination with antithymocyte globulin to decrease adverse effects (eg, allergic reactions and serum sickness). Further, it is an additional immunosuppressive agent. Higher doses or longer duration may be needed if there is serum sickness with ATG. Doses and duration may vary with different protocols.
Adult Dose	5 mg/kg IV days 1-8; then tapered using PO 1 mg/kg days 9-14; further tapering over days 15-29 Stop after 1 mo except in evidence of serum sickness
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; viral, fungal or tubercular skin infections
Interactions	Coadministration with digoxin may increase digitalis toxicity secondary to hypokalemia; estrogens may increase levels of methylprednisolone; phenobarbital, phenytoin and rifampin may decrease levels of methylprednisolone (adjust dose); monitor patients for hypokalemia when taking medication concurrently with diuretics
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Hyperglycemia, edema, osteonecrosis, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, growth suppression, myopathy, and infections are possible complications of glucocorticoid use

Drug Name	Antithymocyte globulin, equine (Atgam)- Inhibits cell mediated immune response either by altering T cell function or eliminating antigen-reactive cells. Little prospective randomized data exist to recommend a single schedule as superior but experience suggests that shorter infusion schedules may be better tolerated.
Adult Dose	100-200 mg/kg IV total dose over variable number of d based on different protocols
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; unremitting leukopenia and/or thrombocytopenia
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Monitor patients for signs of anaphylaxis; keep airway adjuncts and rescue medications at bedside during administration; monitor for signs of infection; administer slowly over at least 4 h via central line to prevent chemical phlebitis

Drug Name	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 growth of normal and neoplastic cells. Monitor carefully; only used on an investigational basis.
Adult Dose	45 mg/kg/d IV for 4 d
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; severely depressed bone marrow function
Interactions	Allopurinol may increase risk of bleeding or infection and enhance myelosuppressive effects; may potentiate doxorubicin-induced cardiotoxicity; may reduce digoxin serum levels and antimicrobial effects of quinolones; chloramphenicol may increase half-life while decreasing metabolite concentrations; may increase effect of anticoagulants; coadministration with high doses of phenobarbital may increase rate of metabolism and leukopenic activity; thiazide diuretics may prolong cyclophosphamide-induced leukopenia and neuromuscular blockade by inhibiting cholinesterase activity
Pregnancy	D - Unsafe in pregnancy
Precautions	Regularly examine hematologic profile (particularly neutrophils and platelets) to monitor for hematopoietic suppression; regularly examine urine for RBCs, which may precede hemorrhagic cystitis

Drug Name	Antithymocyte globulin, rabbit (Thymoglobulin)- May modify T-cell function and possibly eliminate antigen-reactive T lymphocytes in peripheral blood. Dose and duration of therapy vary with different investigational protocols.
Adult Dose	1.5 mg/kg IV qd for 7-14 d; doses up to 3.5 mg/kg for 5 d have also been used
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	To reduce risk of phlebitis, administer only via IV; medical emergency resources should be immediately available to manage rash, dyspnea, hypotension, or anaphylaxis if they develop

Drug Category: Cytokines - Currently, several preliminary studies have shown that the addition of cytokines (eg, G-CSF, GM-CSF) may hasten the neutrophil recovery and may improve the response rate and survival, although long-term use may increase the risk of clonal evolution.

Drug Name	Sargramostim (Leukine, Prokine)- Recombinant human granulocyte-macrophage colony stimulating factor. Capable of activating mature granulocytes and macrophages. Dose and frequency of administration vary with the investigational protocol.
Adult Dose	250 mcg/m2 IV/SC with twice weekly monitoring of CBC
Pediatric Dose	Not established; 5 mcg/kg/d SC has been used in some studies
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Not to use 12-24 h before or 24 h after administering cytotoxic chemotherapy since it will increase sensitivity of rapidly dividing myeloid cells to cytotoxic chemotherapy

Drug Name	Filgrastim (Neupogen)- Granulocyte colony stimulating factor that activates and stimulates production, maturation, migration, and cytotoxicity of neutrophils.
Adult Dose	5 mcg/kg/d SC until ANC has reached 5000/cc
Pediatric Dose	5-10 mcg/kg/d SC
Contraindications	Documented hypersensitivity
Interactions	Not to use 12-24 h before or 24 h after administering cytotoxic chemotherapy since it will increase sensitivity of rapidly dividing myeloid cells
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Risk of developing myelodysplastic syndrome or acute myeloid leukemia in certain patients; leukocytosis; possible tumor growth

FOLLOW-UP

Section 8 of 11

Further Inpatient Care:

• Inpatient care may be needed during periods of infection and for specific therapies such as ATG or BMT.

• Graft-versus-host disease

• Graft failure

Prognosis:

• The outcome of aplastic anemia has significantly improved with time because of better supportive care. The natural history of aplastic anemia suggests that up to one fifth of patients may spontaneously recover with supportive care, but rarely is observational/supportive care therapy indicated by itself. The estimated 5-year survival for the typical patient receiving immunosuppression is 75% and for matched sibling donor BMT is greater than 90%. However, in case of immunosuppression a risk of relapse and late clonal disease exists.

Patient Education:

• Maintenance of hygiene to reduce the risks of infection.
  Stress the need for compliance in the therapy.

MISCELLANEOUS

Section 9 of 11

Medical/Legal Pitfalls:

• Failure to diagnose correctly and initiate appropriate treatment. Aplastic anemia has greater than 70% mortality with supportive care alone. It represents a hematological emergency and care should be instituted promptly.

PICTURES

Section 10 of 11

Caption: Picture 1. Oral leukoplakia in dyskeratosis congenita
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BIBLIOGRAPHY

Section 11 of 11

• Bacigalupo A, Brand R, Oneto R: Treatment of acquired severe aplastic anemia: bone marrow transplantation compared with immunosuppressive therapy--The European Group for Blood and Marrow Transplantation experience. Semin Hematol 2000 Jan; 37(1): 69-80[Medline].
• Bacigalupo A, Broccia G, Corda G: Antilymphocyte globulin, cyclosporin, and granulocyte colony- stimulating factor in patients with acquired severe aplastic anemia (SAA): a pilot study of the EBMT SAA Working Party. Blood 1995 Mar 1; 85(5): 1348-53[Medline].
• Camitta B, O'Reilly RJ, Sensenbrenner L: Antithoracic duct lymphocyte globulin therapy of severe aplastic anemia. Blood 1983 Oct; 62(4): 883-8[Medline].
• de Planque MM, Bacigalupo A, Wursch A: Long-term follow-up of severe aplastic anaemia patients treated with antithymocyte globulin. Severe Aplastic Anaemia Working Party of the European Cooperative Group for Bone Marrow Transplantation (EBMT). Br J Haematol 1989 Sep; 73(1): 121-6[Medline].
• Di Bona E, Rodeghiero,F, Bruno B,: Rabbit antithymocyte globulin (r-ATG) plus cyclosporine and granulocyte colony stimulating factor is an effective treatment for aplastic anaemia patients unresponsive to a first course of intensive immunosuppressive therapy. Gruppo Italiano Trapianto di. Br J Haematol 1999; 107(2): 330-4.
• Frickhofen N, Kaltwasser JP, Schrezenmeier H: Treatment of aplastic anemia with antilymphocyte globulin and methylprednisolone with or without cyclosporine. The German Aplastic Anemia Study Group. N Engl J Med 1991 May 9; 324(19): 1297-304[Medline].
• Horowitz MM: Current status of allogeneic bone marrow transplantation in acquired aplastic anemia. Semin Hematol 2000 Jan; 37(1): 30-42[Medline].
• Kaito K, Kobayashi M, Katayama T: Long-term administration of G-CSF for aplastic anaemia is closely related to the early evolution of monosomy 7 MDS in adults. Br J Haematol 1998 Nov; 103(2): 297-303[Medline].
• Liu, H: Induction of apoptosis in CD34+ cells by sera from patients with aplastic anemia. J Med Sci 1999; 48(2): p. 57-63.
• Marsh J, Schrezenmeier H, Marin P: Prospective randomized multicenter study comparing cyclosporin alone versus the combination of antithymocyte globulin and cyclosporin for treatment of patients with nonsevere aplastic anemia: a report from the European Blood and Marrow Transplant (EBM. Blood 1999 Apr 1; 93(7): 2191-5[Medline].
• Nakao S: Immune mechanism of aplastic anemia. Int J Hematol 1997 Aug; 66(2): 127-34[Medline].
• Piaggio G, Podesta M, Pitto A: Coexistence of normal and clonal haemopoiesis in aplastic anaemia patients treated with immunosuppressive therapy. Br J Haematol 1999 Dec; 107(3): 505-11[Medline].
• Rosti V: The molecular basis of paroxysmal nocturnal hemoglobinuria. Haematologica 2000 Jan; 85(1): 82-7[Medline].
• Scopes J, Daly S, Atkinson R: Aplastic anemia: evidence for dysfunctional bone marrow progenitor cells and the corrective effect of granulocyte colony-stimulating factor in vitro. Blood 1996 Apr 15; 87(8): 3179-85[Medline].
• Socie G, Rosenfeld S, Frickhofen N: Late clonal diseases of treated aplastic anemia. Semin Hematol 2000 Jan; 37(1): 91-101[Medline].
• Stein RS, Means RT, Krantz SB: Treatment of aplastic anemia with an investigational antilymphocyte serum prepared in rabbits. Am J Med Sci 1994 Dec; 308(6): 338-43[Medline].

 

NOTE:

Medicine is a constantly changing science and not all therapies are clearly established. New research changes drug and treatment therapies daily. The authors, editors, and publisher of this journal have used their best efforts to provide information that is up-to-date and accurate and is generally accepted within medical standards at the time of publication. However, as medical science is constantly changing and human error is always possible, the authors, editors, and publisher or any other party involved with the publication of this article do not warrant the information in this article is accurate or complete, nor are they responsible for omissions or errors in the article or for the results of using this information. The reader should confirm the information in this article from other sources prior to use. In particular, all drug doses, indications, and contraindications should be confirmed in the package insert. FULL DISCLAIMER

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