aplastic facts

Aplastic Anemia Home

Navigation Page

New Forum

If aplasticcentral has helped you, please help

FREE Aplastic Book Preview






Start Here

Anemia Basics

Site Listing

Don’t Quit BLOG

Bruce Story

AA White Paper

Short List
Medical Dictionary Social Security 
Alternative Wellness

Aplastic BLOG

AA Forums

Patient Stories



Bone Marrow
Email Bruce

Patient Stories

Add Your Story

Inst of Health


Aplastic Anemia Facts and Statistics

eMedicine World Medical Library
do not influence content.
Use the our online Merriam-Webster medical dictionary.
Ob/Gyn, Psychiatry, and Surgery

Aplastic Anemia

Synonyms, Key Words, and Related Terms: progressive
hypocythemia, aregeneratory anemia, aleukia hemorrhagica,
panmyelophthisis, hypoplastic anemia, toxic paralytic anemia

1 of 11   

Click here to go to the top of this page
Click here to go to the next section in this topic

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
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

Click here to view conflict-of-interest information on the author of this topic
Editor’s Email: David
Aboulafia, MD

eMedicine Journal, June 19 2001, Volume 2, Number

2 of 11   
Click here to go to the next section in this topic
Click here to go to the top of this page
Click here to go to the next section in this topic

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.



  • 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

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.

3 of 11   
Click here to go to the next section in this topic
Click here to go to the top of this page
Click here to go to the next section in this topic

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
  • 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

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.


  • 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

4 of 11   
Click here to go to the next section in this topic
Click here to go to the top of this page
Click here to go to the next section in this topic

Lymphoblastic Leukemia

Acute Myelogenous

Agnogenic Myeloid
Metaplasia with Myelofibrosis

Herpesvirus Type 6 (HHV-6)






Other Problems to be Considered:

Multiple myeloma

Congestive splenomegaly resulting in hypersplenism


Disseminated lupus erythematosus

Infectious etiology such as HIV, mycobacterial infections,
cytomegalovirus (CMV), EBV

WORKUP Section
5 of 11   
Click here to go to the next section in this topic
Click here to go to the top of this page
Click here to go to the next section in this topic

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
  • 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
  • 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.


  • Review of peripheral smear
  • Bone marrow aspiration and biopsy

Histologic Findings: Findings include hypocellular
bone marrow with fatty replacement and relatively increased
nonhematopoietic elements such as plasma cells and mast cell.
Perform careful examination to exclude metastatic tumor foci on

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

  • Blood
  • Neutrophils – Less than 0.5×10’9/L
  • Platelets – Less than 20×10’9/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 0.2×10’9/L constituted a very
    severe aplastic anemia (VSAA) group. This group is less likely
    to respond to immunosuppressive therapy.

6 of 11   
Click here to go to the next section in this topic
Click here to go to the top of this page
Click here to go to the next section in this topic

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

    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.


  • 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

7 of 11   
Click here to go to the next section in this topic
Click here to go to the top of this page
Click here to go to the next section in this topic

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

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

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

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
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

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

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
(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

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

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

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

8 of 11   
Click here to go to the next section in this topic
Click here to go to the top of this page
Click here to go to the next section in this topic

Further Inpatient Care:

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

Further Outpatient Care:

  • Frequent outpatient follow-up is needed for monitoring blood
    counts and adverse effects of various drugs. Packed red blood
    cell and platelet transfusions also are given on an outpatient

In/Out Patient Meds:

  • Specific medications would depend on the choice of therapy and
    whether it is supportive care only, immunosuppressive therapy,
    or bone marrow transplantation.


  • Patients with aplastic anemia should be treated by physicians
    who are expert in the care of immunocompromised patients and in
    consultation with a BMT physician in patients younger than 65


  • Infections
  • Bleeding
  • Complications of BMT
  • Graft-versus-host disease
  • Graft failure


  • 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.

9 of 11   
Click here to go to the next section in this topic
Click here to go to the top of this page
Click here to go to the next section in this topic

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.

10 of 11   
Click here to go to the next section in this topic
Click here to go to the top of this page
Click here to go to the next section in this topic

Picture 1. Oral leukoplakia in dyskeratosis congenita
Click to see larger picture Click to see detailView
Full Size Image
Click to ZoomeMedicine
Zoom View (Interactive!)
Picture Type:

11 of 11   
Click here to go to the next section in this topic
Click here to go to the top of this page

  • 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
  • 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):
  • 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):
  • 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):
  • 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].




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.

eMedicine Journal, June 19 2001, Volume 2, Number

© Copyright 2001, eMedicine.com, Inc.


> Medicine,
Ob/Gyn, Psychiatry, and Surgery
> Hematology

>Aplastic Anemia
email us with any
comments you have on our new chapter format.
Use the our online Merriam-Webster medical dictionary.



There are only 300 new
cases of Aplastic Anemia reported each year.

Aplastic anemia
and myelodysplastic syndromes can strike any person of any age,
of any gender or any race, of any neighborhood anywhere in the world. In
the United States, thousands of men, women and children are stricken
with these non-contagious and often fatal blood disorders every year.
They occur when the bone marrow stops making enough healthy blood cells.
In most cases the cause of the diseases is idiopathic (unknown.)
The suspected causes are many: radiation, benzene-based
compounds, viruses such as hepatitis; environmental toxins; over the
counter and prescription medications; street drugs; and other many
chemicals too numerous to list.

Aplastic anemia
can be traced as far back as 1888 when a famous German pathologist, Dr.
Paul Ehrlich, studied the case of a pregnant woman who died of bone
marrow failure. It wasn’t until 1904 that this disorder was termed
aplastic anemia. Because it is not a reportable disease there is no way
of knowing of the incidence of the disease. It is estimated that there
are 2 new cases per million population (496) each year in the United
States, though some doctors feel this number is extremely low. The
Aplastic Anemia & MDS International Foundation is one of the only
organizations in the world maintaining a voluntary Patient
to keep track of patients for statistical analysis.

syndromes (MDS)
were first described as pre-leukemic conditions in
the early 1930’s and weren’t treated as a separate group of disorders
until 1976. Because these also are not reportable diseases, it is very
difficult to state the exact incidence. The Aplastic Anemia & MDS
International Foundation maintains a voluntary Patient
for statistical analysis. It is believed that there are
approximately 10,000 to 20,000 new cases each year in the United States
with the number increasing each year because of exposure to radiation
and other toxins. These are relatively new diseases; therefore the
number of diagnosed cases is increasing. The highest incidence is in
patients over 60 years of age though people of all ages, including
children, are diagnosed with it each year.

Aplastic anemia
and myelodysplastic syndromes appear to be more common in Asia
than in the United States. A formal epidemiological study was conducted
by the National Heart, Lung & Blood Institutes of the National
Institutes of Health in Thailand that confirms this to be true for
aplastic anemia. It is also suspected that these two diseases are more
common in Russia and Vietnam, as well as the countries of Mexico,
Africa, India and South America.

Many celebrities
have been stricken with
and myelodysplastic syndromes. Madame Curie and
Eleanor Roosevelt succumb to aplastic anemia and more recently Carl
Sagan and Senator Paul Tsongsas fought myelodysplastic syndromes.

Aplastic anemia
has been an intriguing disease not only for the medical community, but
for the entertainment industry as well. Best-selling author, Patricia
Cornwall included it in her best selling murder mystery "All That
Remains." Many television shows have featured Aplastic Anemia
patients such as: "ER", "Touched By An Angel",
"Sisters", "Bay Watch", "Emergency 911",
"Days of Our Lives", "Loving", "General
Hospital", "Gideon’s Crossing" and "Strange
World." In 1934, a black & white movie entitled "Murder on
the Blackboard" starring Edna May Oliver and Bruce Cabot featured a
man who was poisoned by daily doses of benzene to create ‘pernicious
anemia of the bones,’ or aplastic anemia.

Aplastic Anemia & MDS International Foundation, Inc.

P.O. Box 613
Annapolis, Maryland

410.867.0242 aamdsoffice@aol.com

Extracts & Statistics from Other Sources

Updated May 8, 2002 Courtesy of
Randy Ramage who sadly succumbed due to a virus on March 22, 2002
following BMT .  He found much more optimistic results and made the
decision to go forward. 

Hi Bruce,

I told you my Dr. (Dr. Judith Marsh) was on the board of the International
BMT registry and the European BMTR and was going to send
info on their BMT success rate records. By the way, noticed you have

an artical of hers in your "Current" section
under "Walsh".
She sent 3 graphs but
they are all a bit out of date I feel so didn’t
them and send them off to you. All BMTs are from HLA identical

The IBMTR graph shows relative survival rates of BMTs comparing with
1976-80 with1981-87 and 1988-92. 1976-80
shows about a 50% survival.
1981-87 shows about a
64% survival.
1988-92 shows about a 69% survival.

The EBMTR shows two comparative graphs. One on immunosuppression
and the other on BMTs. The
immunosuppression therapy graph compares survival rates between 1981

and 1991 1981 shows about a 59%
survival rate
1991 shows about a 75% survival rate
The Bone Marrow transplant graph (HLA identical siblings)
also compares
survival rates between 1981 and 1991
1981 shows about a 55% survival rate 1991
shows about a 78% survival rate

She also sent a more recent graph from the Fred Hutchinson Cancer
Research Center comparing 1970-75 with 1976-1988 and
1970-75 shows about a 50% survival
rate up to about 15 years. This then
drops off to
1976-88 shows about a 60% survival rate which
over 20 years drops off to
65% 1988-97
shows about an 85% survival rate which is maintained for 10

Seeing as how the most recent information was at the Fred Hutchinson
Center, I searched the net and found Cyclophosphamide
and Antithymocyte Globulin to Condition Patients With
Anemia for Allogeneic Marrow Transplantations: The Experience
Four Centers
which is an October 13th 2000 Report.
This gives more current graphs
and shows an 88%
survival rate using the same standard BMT regimen as is
now on ages between 2 and 59. It can be found at


What I found interesting about this report is
that it deals with 93 cases and gives
information on how and when each of the none survivors died. Almost

entirely from infections which are named in the report.
It also shows
the % chance of getting GVHD and at
what level ie. Grade 1, 11, 111 or
1V (1V being
the most severe). The graphs are also quite good. At the
least the information has made me more determined to avoid sources

of infection and follow the Neutropenic (or Clean) Diet.
Whether I opt
for the BMT or the High dose Cytoxin,
the main cause of death is the
that got out of control.


Transplant Outcomes for Non-Leukemias – Article from


Severe Aplastic Anemia

Myelodysplastic & Related Syndromes

Non-Hodgkin’s Lymphoma

Other Non-Malignant Diseases
# of






4-Year Survival*

36% ± 7%

26% ± 4%

24% ± 7%

43% ± 5%
from Aplastic Anemia Pathophysiology
and Treatments P,
266,  ISBN 0-521-64101-2 Copyright 2000 Edited by Hubert
Schrezenmeier, Professor of Medicine Free University of

Article –   Alternative Donor Bone
Marrow Transplantation Jill Hows, et. al.

Long Term Survival Rates of BMT for HLA
Matched SIbling = 75%, Alternate Family Member 50%, MUD = 35%.
From Same Source as Above:

P, 268, ff extracts –  "This is the largest analysis of
alternative donor BMT for SAA so far reported. The transplant era
1986-95 was chosen to include cases which were recent enough to reflect
current protocals and supportive care but with long enough follow-up to
allow meaningful analysis.  … There was surprisingly little
evidence fro an impact of recipient age on survival after alternative
donor BMT in this analysis (my note – hang in there you "older
types" like me)… The promising results of the Milwaukee Group
using T-Cell Depletion require confirmation by other centers.  The
probability of 5-year survival after immunosuppressive treatment has
improved in the past decade. In a recent study, patients who were
treated with a combination of ATG, cyclosporin and granulocyte cologny-stimulating
factor (G-CSF) had an 85 % probability of 3-year survival.  

The optimal protocol for alternative donor BMT for SAA cannot be
established from this analysis. It is not certain whether limited field
irradiation or total body irradiation in pre-transplant preparation
reduces graft failure in unrelated donor BMT.  … At this time,
alternative donor BMT is not recommended as a first-line treatment for
patinest with SAA who lack an HLA-identical sibling.  Patients who
lack an HLA-identical sibling should receive some form of
immunosuppression as initial therapy. 


The decision to proceed with alternative donor BMT is
complex.  Hematologists are encouraged to discuss cases wutg
cebtere specializing in the management of SAA. The correct timing of
alternative donor BMT, the upper age limit for recipients and the level
of acceptable mismatch have not been defined.  The authors
recommend that alternative donor BMT be conisidered within 6 months of
the diagnosis of SAA in patients who are less than 30 years of age and
have not responded to immunosuppresive therapy. 


1: Acta Haematol 2000;103(1):19-25
Current results of bone marrow transplantation in patients with acquired severe
aplastic anemia. Report of the European Group for Blood and Marrow
transplantation. On behalf of the Working Party on Severe Aplastic Anemia of the
European Group for Blood and Marrow Transplantation.
Bacigalupo A, Oneto R, Bruno B, Socie G, Passweg J, Locasciulli A, Van Lint MT,
Tichelli A, McCann S, Marsh J, Ljungman P, Hows J, Marin P, Schrezenmeier H.
Second Department of Haemotology, Ospedale San Martino, Servizio Radioterapia
IST, Genoa, Italy. apbacigalupo@smartino.ge.it
We have analyzed 2,002 patients grafted in Europe between 1976 and 1998 from an
identical twin (n = 34), from an HLA-identical sibling (n = 1,699) or from an
alternative donor (n = 269), which included unrelated and family mismatched
donors. The proportions of patients surviving in these three groups are,
respectively, 91, 66 and 37%: major causes of failure were acute graft-versus
host disease (GvHD) (11%), infection (12%), pneumonitis (4%), rejection (4%). In
multivariate Cox analysis, factors predicting outcome were patient's age (p <
0.0001), donor type (p < 0.0001), interval between diagnosis and bone marrow
transplantation (BMT) (p < 0.0005), year of BMT (p = 0.0005) and female donor
for a male recipient (p = 0.02). Patients were then divided in two groups
according to the year of BMT: up to or after 1990. The overall death rate
dropped from 43 to 24% (p < 0.00001). Improvements were seen mostly for grafts
from identical siblings (from 54 to 75%, p < 0.0001), and less so for
alternative-donor grafts (from 28 to 35%; p = 0.07). Major changes have occurred
in the BMT protocol: decreasing use of radiotherapy in the conditioning regimen
(from 35 to 24%; p < 0.0001) and increasing use of cyclosporin (with or without
methotrexate) for GvHD prophylaxis (from 70 to 98%; p < 0.0001). In conclusion,
the outcome of allogeneic BMT for patients with severe aplastic anemia has
considerably improved over the past two decades: young patients, grafted early
after diagnosis from an identical sibling, have currently an over 80% chance of
long-term survival. Transplants from twins are very successful as well. The risk
of complications with alternative donor transplants is still high. Copyright
2000 S. Karger AG, Basel
PMID: 10705155 [PubMed - indexed for MEDLINE]
1: Ann Intern Med 1999 Feb 2;130(3):193-201
Comment in:
 Ann Intern Med. 1999 Oct 19;131(8):633-4
Effectiveness of immunosuppressive therapy in older patients with aplastic
anemia. European Group for Blood and Marrow Transplantation Severe Aplastic
Anaemia Working Party.
Tichelli A, Socie G, Henry-Amar M, Marsh J, Passweg J, Schrezenmeier H, McCann
S, Hows J, Ljungman P, Marin P, Raghavachar A, Locasciulli A, Gratwohl A,
Bacigalupo A.
Department Zentrallabor, Kantonsspital Basel, Switzerland.
BACKGROUND: Immunosuppressive therapy has been used for successful treatment of
severe aplastic anemia, but little information is available on outcome in older
patients. OBJECTIVE: To evaluate outcome in patients older than 50 years of age
who received immunosuppressive therapy for aplastic anemia. DESIGN:
Retrospective cohort study. SETTING: 56 centers of the European Group for Blood
and Marrow Transplantation (EBMT). PATIENTS: 810 patients with aplastic anemia
reported between 1974 and 1997. Patients were evaluated according to age group:
60 years of age or older (n = 127), 50 to 59 years of age (n = 115), and 20 to
49 years of age (n = 568; reference group). INTERVENTION: Antilymphocyte
globulin, cyclosporine, or both. MEASUREMENTS: Survival, cause of death,
response to treatment, relapse rate, and risk for late complications were
analyzed in all patients and by age group. RESULTS: The 5-year survival rate was
57% (95% CI, 46% to 66%) in patients 50 to 59 years of age and 50% (CI, 39% to
60%) in patients 60 years of age or older compared with 72% (CI, 68% to 76%) in
patients younger than 50 years of age (P < 0.001). Response to therapy, relapse
rate, and risk for clonal complications were similar in all three age groups (P
> 0.2). Age was significantly associated with an increased risk for death
(relative risk compared with patients 20 to 49 years of age, 1.80 [CI, 1.29 to
2.52] for patients 50 to 59 years of age and 2.57 [CI, 1.87 to 3.53] for
patients > or = 60 years of age), mainly because of bleeding or infection (P =
0.02). Response to immunosuppressive therapy in all patients at 12 months was
62% (CI, 58% to 66%); no difference was seen among the age groups in
multivariate analysis (P > 0.2). Sixty-six of the 379 responding patients (17%)
subsequently had relapse. The risk for clonal disorders at 10 years was 20% (CI,
15% to 27%). CONCLUSIONS: Response to immunosuppression in aplastic anemia is
independent of age, but treatment is associated with increased mortality in
older patients.
PMID: 10049197 [PubMed - indexed for MEDLINE]
1: J Clin Oncol 2001 Feb 15;19(4):1152-9
CD6+ donor marrow T-cell depletion as the sole form of graft-versus-host disease
prophylaxis in patients undergoing allogeneic bone marrow transplant from
unrelated donors.
Soiffer RJ, Weller E, Alyea EP, Mauch P, Webb IL, Fisher DC, Freedman AS,
Schlossman RL, Gribben J, Lee S, Anderson KC, Marcus K, Stone RM, Antin JH, Ritz
Department of Adult Oncology, Dana-Farber Cancer Institute, Boston, MA 02115,
USA. robert_soiffer@dfci.harvard.edu
PURPOSE: The role of donor marrow T-cell depletion (TCD) in preventing
graft-versus-host disease (GVHD) after transplantation of unrelated allogeneic
marrow remains undefined. Because different TCD methodologies differ in the
degree and specificity with which T cells are removed, it is likely that
transplant outcomes would depend on which technique is used. Herein, we report
results in the first 48 recipients of unrelated marrow using CD6+ TCD as the
sole form of GVHD prophylaxis. PATIENTS AND METHODS: Median age of patients was
46 years (20 to 58 years). Donors were matched at A/B HLA loci. Ablation
consisted of cyclophosphamide and fractionated total-body irradiation (TBI; 14
Gy). To facilitate engraftment, patients also received 7.5 Gy (22 points) or 4.5
Gy (26 points) of total lymphoid irradiation (TLI) before admission. No
additional immune suppressive prophylaxis was administered. Granulocyte
colony-stimulating factor was administered daily from day +1 to engraftment.
RESULTS: All 48 patients demonstrated neutrophil engraftment. An absolute
neutrophil count of 500 x 10(6)/L was achieved at a median of 12 days (range, 9
to 23 days). There were no cases of late graft failure. The number of CD34+
cells infused/kg was associated with speed of platelet and neutrophil recovery.
The dose of TLI did not influence engraftment. Grades 2-4 acute GVHD occurred in
42% of patients (95% confidence interval [CI], 0.28 to 0.57). Mortality at day
100 was 19%. There have been only five relapses. Estimated 2-year survival was
44% (95% CI, 0.28 to 0.59) for the entire group, 58% for patients less than 50
years of age. In multivariable analysis, age less than 50 years (P =.002),
cytomegalovirus seronegative status (P =.04), and early disease status at bone
marrow transplant (P =.05) were associated with superior survival. CONCLUSION:
CD6+ TCD does not impede engraftment of unrelated bone marrow after low-dose
TLI, cyclophosphamide, and TBI. CD6+ TCD as the sole form of GVHD prophylaxis
results in an incidence of GVHD that compares favorably with many adult studies
of unrelated transplantation using unmanipulated marrow and immune-suppressive
medications, especially in light of the median age of our patients (46 years).
Although event-free survival in patients less than 50 years of age is very
encouraging, older patients experience frequent transplantation-related
complications despite TCD.
Publication Types:
Clinical trial
PMID: 11181681 [PubMed - indexed for MEDLINE]
1: Biol Blood Marrow Transplant 2000;6(1):35-43
Aerosolized pentamidine as pneumocystis prophylaxis after bone marrow
transplantation is inferior to other regimens and is associated with decreased
survival and an increased risk of other infections.
Vasconcelles MJ, Bernardo MV, King C, Weller EA, Antin JH.
Department of Adult Oncology, Dana-Farber Cancer Institute, Boston,
Massachusetts 02115, USA. michael_vasconcelles@dfci.harvard.edu
Pneumocystis carinii pneumonia (PCP) is a life-threatening but preventable
infection that may occur after bone marrow transplantation (BMT). Although
various prophylactic regimens have been used in this setting to prevent active
infection, their efficacy, toxicity profile, and impact on outcomes are poorly
described in this patient group. We undertook a retrospective cohort study in
which we reviewed the records of 451 adult patients who underwent BMT for
hematologic malignancies, aplastic anemia, or myelodysplasia over a 7-year
period at the Brigham and Women's Hospital. Post-BMT PCP prophylaxis consisted
of aerosolized pentamidine (AP) 150 mg every 2 weeks or 300 mg per month,
trimethoprim/sulfamethoxazole (TMP/SMX) 160/800 mg orally b.i.d. 3 times per
week, or dapsone 100 mg orally each day. Prophylaxis was continued for 1 year
post-BMT in all patients when clinically feasible. One hundred twenty-one
patients were unevaluable because of death or relapse <60 days after BMT (n =
89), loss to follow-up upon hospital discharge (n = 20), or other reasons (n =
12). Three eligible patients did not receive any prophylaxis and were not
further evaluated. Of the 327 patients analyzed, 133 underwent autologous BMT, 4
syngeneic BMT, 159 related allogeneic BMT, and 31 unrelated allogeneic BMT.
Graft-versus-host disease prophylaxis in the 190 patients receiving allogeneic
BMT consisted of T-cell depletion with anti-CD5 and complement in 58 patients
and cyclosporine/methotrexate or FK506 with or without steroids in 132 patients.
Eight of 327 (2.4%) documented PCP cases were identified, 0 of 105 in patients
receiving only TMP/SMX. Four cases occurred in patients receiving only AP (4/44,
9.1%; odds ratio [OR] relative to TMP/SMX 23.4, 95% confidence interval [CI]
1.2, 445.2); 1 in patients receiving only dapsone (1/31, 3.2%; OR not
significant); 2 in patients receiving more than 1 prophylactic regimen (2/147
1.4%; OR not significant); and 1 >1 year post-BMT in a patient who was off PCP
prophylaxis. Although the patients receiving only AP had a significantly lower
probability of treatment-related toxicity than those receiving TMP/SMX (OR 0.19
[95% CI 0.04, 0.851), the probability of their acquiring other serious non-PCP
infections was increased (OR 2.2 [95% CI 1.0, 4.6]), and the probability of
their dying by 1 year post-BMT was significantly higher (OR 5.2 [95% CI 2.4,
26.6]), even when adjusted for variables such as type of BMT (autologous versus
allogeneic; high versus low risk) and sex. Although AP is associated with fewer
toxicities, the data show that it is inferior to TMP/SMX in preventing PCP in
the post-BMT setting and is associated with an increased risk of other
infections and a higher mortality at 1 year after BMT.
Publication Types:
Clinical trial
PMID: 10707997 [PubMed - indexed for MEDLINE]
  • ·Aplastic anemia and myelodysplastic syndromes are non-contagious
    blood diseases that can strike regardless of age, gender, race or
    geographic location. They occur when bone marrow stops making enough
    healthy blood cells.
  • ·Estimates put new cases of aplastic anemia at only 300
    per year
    and of MDS at 20,000 per year. The diseases are
    too rare to be reported to public health agencies such as the
    Centers for Disease Control and Prevention. But AA&MDSIF keeps a
    patient registry database, one of the few sources for statistical
    information on the diseases.
  • ·The most common treatments are transfusions, drugs that suppress
    the immune system and bone-marrow transplants. While transplants
    have effected some cures, a bone-marrow match is hard to find; even
    among relatives, an exact match occurs only about a third of the
  • ·Many cases have been linked to exposure to toxic chemicals or
    radiation. Some have a genetic component, and some are the result of
    the body’s reaction to a virus or infection. In most cases, the
    cause is unknown.


AA is rare with a worldwide variable annual incidence
cited between 2 and 6 cases per million persons. Various studies have been
done to determine the prevalence in defined populations. The International
Aplastic Anemia and Agranulocytosis Study determined the frequency in
Europe and Israel to be 2 cases per million in the early 1980s. Between
May, 1984 and April, 1987, a study conducted in France placed that
country’s annual incidence at 1.5 per million. A geographic variation can
be noted: studies conducted in China and Bangkok describe overall annual
incidences of 0.74 per hundred thousand and 3.7 per million, respectively.
It is undisputed that the disease is more prevalent in the Orient than in
the Western world. Age and gender distribution vary with geographic
location as well . In the U.S. and Europe, most cases occur in either the
15-24 year age group, or in those > 60 years old. In Bangkok, the
greatest number of cases were in the 15-24 year range as well; China,
however, reports a peak for women > 50 years and men > 60 years. Men
in France have two peaks, one at 15-30 years and a second at > 60
years, while the greatest risk for women was > 60 years old. Males also
typically have a more severe course than females. The explanations for the
age and gender differences may be some occupational risk, while the
geographical variance suggests an environmental influence.

B. Davis


CREATED: 6/24/94, LAST MODIFIED: 4/24/96, UT DPALM MEDIC, copyright


> Programmed
cell death
as signalled by the nuclei in normally functioning human
and animal cells
when age or state
of cell health
and condition

An active process
requiring metabolic
activity by
the dying cell,
often characterised by cleavage
of the DNA into
fragments that give a so called laddering
pattern on gels.

Cells that die
by apoptosis do not usually elicit the inflammatory
that are associated
with necrosis,
though the reasons
are not clear.

Cancerous cells,
however, are
unable to experience the normal
cell transduction
or apoptosis-driven natural
cell death process.

See: ced
, bcl.

(18 Nov 1997)


Previous: apoplast,
apoplexy, apoprotein,
, apoprotein

Next: aporosa,
aporose, apositic,
apostate, apostemate,

© On-line
Medical Dictionary


H Reports on High Dose
Cytoxan for AA

December 6, 2000 — Tisdale & colleagues, Hematology
Branch, National Heart, Lung, and Blood Institute, National Institute of
Health (NIH), report on randomized trial of high dose cyclophosphamide (Cytoxan)
for AA patients in a recent issue of The Lancet. 31 patients were
enrolled, 15 assigned cyclophosphamide and 16 were assigned ATG. Both
received cyclosporine. The trial was terminated prematurely after 3 early
deaths in the cyclophosphamide group. No significant differences at 6
months after treatment in the overall response rate. Author abstract
available through
Tisdale JF, et al. "High-dose cyclophosphamide in severe aplastic
anemia: a randomized trial." The
, Nov 4, 2000. Vol 356, no 9241, p 1554.


New Protocol at NIH-NHLBI

May 30, 2000 — National Institutes of Health, National
Heart, Lung and Blood Institute, in Bethesda Maryland, informed us of
their new protocol for severe aplastic anemia on presentation, consisting
of combined ATG, cyclosporine (for 6 months), and mycophenolate mofetil
(for 18 months). It is well tolerated and appears to lead to meaningful
clinical responses in at least as high a proportion of cases as does
conventional ATG plus CSA. Only 12 patients have been treated to date
here. Of note, responses appear to be more rapid and have surprisingly
occurred in several patients with "super-severe" disease where
neutrophil counts are close to zero.

To find out more about this protocol, call Wanda Zamani at 301-402-0764 or
contact be email


Irradiated Blood Products
& Leukocyte Filters for AA/MDS Patients

February 1, 2000 — Screening out damaging leukocytes
with leukocyte blood filters is essential to minimized adverse reactions
following blood transfusions. Low-level radiation also reduces the amount
of lymphocytes in blood, reducing the risk of transfusion-associated
graft-versus-host disease. For optimum results, both processes should have
been carried out on the blood for your transfusion, but you will need to
check this at the time of ordering, and ask the nurse to check again at
the bedside. In addition, try for blood that has been leukocyte-filtered
before storage, rather than filtered at the bedside. The former is more
efficiently filtered. There are no known negative side-effects to blood
treated in these ways. A spokesperson at America’s Blood Centers stated
that insurance companies generally accept the need for these products when
fighting aplastic anemia and MDS. Our thanks to AA&MDISF member Bob
Carroll for providing this information.

The National Organization for Rare
Disorders, Inc.

Thank you. Your order has been processed.



Anemia, Aplastic

Copyright (C) 1986, 1987, 1988, 1990, 1991, 1992,
1993, 1995, 1996, 1997, 1998, 1999 National Organization for Rare
Disorders, Inc.


It is possible that the main title of the report (Aplastic Anemia)
is not the name you expected. Please check the SYNONYMS listing to
find the alternate name(s) and disorder subdivision(s) covered by
this report.


Aregenerative Anemia


Hemorrhagica Aleukia

Hypoplastic Anemia



Progressive Hypoerythemia

Refractory Anemia

Toxic Paralytic Anemia

Disorder Subdivisions:  

Information on the following diseases can be found in the
Related Disorders section of this report:

Fanconi’s Anemia

Dyskeratosis Congenita

Anemias, Other

General Discussion  


The information contained in the Rare Disease Database is provided
for educational purposes only. It should not be used for
diagnostic or treatment purposes. If you wish to obtain more
detailed information about this disorder, please contact your
personal physician and/or the agencies listed in the
"Resources" section this report.

Aplastic Anemia is a rare bone marrow disorder characterized by
decreased function of the bone marrow that results in abnormally
low levels of all the cellular elements of the blood (pancytopenia).
In some cases, the disorder may affect primarily single cell lines
(i.e., red blood cells, white cells, or platelets). The initial
symptoms may include increasing weakness, fatigue, recurrent or
persistent infections, and/or bleeding. In about 50 percent of
cases, the exact cause is not known. In some cases, certain toxic
agents (e.g., inorganic arsenic) or drugs (e.g., phenylbutazone,
choramphenicol, etc.) may cause Aplastic Anemia.



The symptoms of Aplastic Anemia may begin suddenly, but in most
cases they appear gradually. The initial symptoms of Aplastic
Anemia may include increasing weakness, fatigue, recurrent or
persistent infections, and/or lethargy. Physical activity may be
followed by headache and/or difficulty breathing. An individual
with this disorder may get frequent bacterial infections and/or be
sicker than is normal for that particular infection. Nosebleeds
and/or bleeding under the skin are also common.

The symptoms of Aplastic Anemia are dependent on the extent of the
reduced number of all blood cells (pancytopenia) or the type of
blood cell(s) that are affected.



In about 50 percent of cases of Aplastic Anemia, the disease has
no apparent cause. Certain toxic agents that may cause the
disorder include inorganic arsenic and certain drugs such as
phenylbutazone, chloramphenicol, other antibiotics, azathioprine,
carbamazepine, carbonic anhydrase inhibitors, dapsone,
ethosuximide, gluthethimide, gold compounds, penicillamine,
pentoxifylline, probenecid, quinacrine, sulfonamides,
sulfonylureas, trimethadione, and anticonvulsants. High doses of
radiation may also cause marrow failure but this is not usually
classified as aplastic anemia.

The symptoms of Aplastic Anemia are the result of the loss of
primitive cells (stem cells) in the bone marrow that are the
precursors (forerunners) of more mature blood cells. A majority of
cases of aplastic anemia appear to be caused by activation of the
immune system with secondary damage to the marrow.

Affected Population  

Aplastic Anemia is a rare bone marrow disorder that affects males
and females in equal numbers. This disorder affects approximately
1.5 to 2 in 1,000,000 people in the United States; approximately
500 to 1,000 new cases are reported each year. Acquired Aplastic
Anemia affects children slightly less frequently than adults.
However, children may also develop the disease from the less
frequent inherited causes of bone marrow failure.

Related Disorders  

Symptoms of the following disorders can be similar to those of
Aplastic Anemia. Comparisons may be useful for a differential

Fanconi’s Anemia is an inherited disorder characterized by
abnormalities of the heart, kidneys, skeleton, and other body
systems. Failure of the bone marrow to produce adequate blood
cells and platelets may develop at any age but most frequently
occurs at the end of the first decade of life. The initial
symptoms of Fanconi’s Anemia may be easy bruising and unexplained
nosebleeds (epistaxis). Fanconi’s Anemia is inherited as an
autosomal recessive genetic trait. (For more information on this
disorder, choose "Fanconi’s Anemia" as your search term
in the Rare Disease Database.)

Dyskeratosis Congenita is a rare disorder characterized by
darkening and/or unusual absence of skin color (hyper/hypopigmentation),
abnormal changes in the nails (dystrophy), and progressive
degenerative changes of the mucous membranes (leukoplakia) that
line the anus, urethra, lips, mouth, and/or eyes. This disorder
may be inherited or occur sporadically. (For more information on
this disorder, choose "Dyskeratosis Congenita" as your
search term in the Rare Disease Database.)

Other types of anemias include: Megaloblastic Anemia, Warm
Antibody Hemolytic Anemia, Cold Antibody Hemolytic Anemia,
Acquired Autoimmune Hemolytic Anemia, Pernicious Anemia, Folic
Acid Deficiency Anemia, Blackfan- Diamond Anemia, Hereditary
Nonspherocytic Hemolytic Anemia, Hereditary Spherocytic Hemolytic
Anemia, and Sickle Cell Anemia. (For information on other types of
Anemias, choose "Anemia" as your search term in the Rare
Disease Database.)

Other diseases with symptoms of failure of the bone marrow to
produce sufficient blood cells may also occur in renal failure,
liver diseases, endocrine abnormalities, late-stage malignancies
(particularly with metastasis to the bone marrow), chronic
infections, and certain hereditary diseases.


Standard Therapies  

When Aplastic Anemia is thought to be caused by exposure to
chemicals or drugs, the toxic source must be removed or
eliminated. If a drug is known to cause Aplastic Anemia (e.g.,
certain anticonvulsants), the prescribing physician will require
affected individuals to take periodic blood tests so the drug can
be discontinued if there are signs of bone marrow suppression.
Since individuals affected by a severe form of Aplastic Anemia are
susceptible to recurring infections, they should seek medical
attention with any illness accompanied by a fever.

The most effective initial treatment for aplastic anemia depends
upon the patient’s age. For patients less than 30 years of age,
the most effective treatment for Aplastic Anemia is bone marrow
transplant from a matched related donor. An affected
individual’s closest relatives should be tissue-typed. In 20 to
30 percent of patients, a brother or sister of the individual may
be a compatible donor. Blood transfusions before a transplant
should be done only if absolutely necessary since they lower the
chances of successful transplantation. If a bone marrow transplant
is a possibility, then the affected individual’s family members
should not be used for blood transfusions. Aspirin and other drugs
that may cause platelet dysfunction should be avoided.

In patients 30 years of age or older, initial treatment with
immunosuppressive drugs is the treatment of choice. A combination
of drugs that suppress the immune system (e.g. antilymphocyte
globulin, prednisone, and cyclosporin) may result in an
improvement of bone marrow function in 70 to 80 percent of
individuals with Aplastic Anemia. The use of granulocyte colony
stimulating factors (GCSF or GMCSF) may decrease infectious
complications while the patient begins to respond to immune
suppression. Responses to immune suppressive drugs are usually not
as complete or as long lasting as responses to bone marrow

Investigational Therapies  

A phase III clinical study is underway to determine the long-term
safety and effectiveness of cyclophosphamide (cytoxan) for the
treatment of Aplastic Anemia. High doses of the drug are
administered over four days, followed by either three months of
cyclosporine or no cyclosporine. More studies are needed to
determine the long-term safety and effectiveness of this drug
regimen for the treatment of Aplastic Anemia. For more
information, contact:

Marlene & Stewart Greenbaum Cancer Center

University of Maryland

22 South Greene Street

Baltimore, MD 21201

Attn: Meyer Heyman, M.D.

(410) 328-2594

High-dose cyclophosphamide and G-CSF (granulocyte-colony
stimulating factor) are being studied for the treatment of
Aplastic Anemia. Newly diagnosed and previously treated
individuals with severe Aplastic Anemia (who are not candidates
for bone marrow transplantation) may be eligible for this study.
For more information, contact:

Johns Hopkins Oncology Center

600 North Wolfe Street

Baltimore, MD 21287

Robert Brodsky, M.D.

(410) 614-2809


Richard Jones, M.D.

(410) 955-2815

The orphan drug Etiocholanedione is being studied for the
treatment of Aplastic Anemia. More studies are needed to determine
the long-term safety and effectiveness of this drug for the
treatment of Aplastic Anemia. For more information, contact the

SuperGen, Inc.

3158 Des Plaines Avenue, Suite 10

Des Plaines, IL 60018

Early studies are underway to test the use of the steroid hormone
etiocholanedione (ED) for treatment of Aplastic Anemia. More
studies are needed to determine the long-term safety and
effectiveness of this drug for the treatment of Aplastic Anemia.
For more information, contact:

University of Texas-Houston Medical School

6431 Fannin

PO Box 20708

Houston, TX 77225

(713) 792-5450

Attn: Harinda S. Juneja, M.D.

The National Institutes of Health is conducting a laboratory study
regarding the incidence of Aplastic Anemia after infection. For
more information, contact:

National Institutes of Health

National Heart, Lung & Blood Institute

Building 10-7, Room C103

Bethesda, MD 20892

(301) 496-5093

Attn: Neal S. Young, M.D.

Laboratory studies are being conducted on blood and marrow to
determine the cause or origin (etiology) of Aplastic Anemia. For
more information, contact:

Dana Farber Cancer Institute


44 Binney Street

Boston, MA 02115

(617) 632-4932

Attn: Eva Guinan, M.D.

Dr. Gary Pekoe is conducting a phase I clinical trial of RII
Retinamide for the treatment of refractory aplastic anemia. More
studies are needed to determine the long-term safety and
effectiveness of this treatment. For more information, contact:

Gary Pekoe, M.D.

Long Beach VA Hospital

5901 E Seventh St

Long Beach, CA 90822

(800) 321-2466

The Children’s Hospital of Pittsburgh is conducting a randomized
clinical trial comparing the use of immunosuppression (ATG and
cyclosporine) and granulocyte-macrophage colony-stimulating factor
(GM-CSF) to an investigational hematopoietic cytokine
immunosuppressor (PIXY321) for the treatment of acquired severe
Aplastic Anemia. Individuals who are eligible to participate in
this study must be between one and 21 years of age and previously
untreated. For more information, contact:

Jeffrey Hord, M.D.

Children’s Hospital of Pittsburgh

3520 Fifth Ave

Pittsburgh, PA 15213

(412) 692-5055

A phase III clinical trial is underway to compare the use of
cylcophosphamide versus cylcophosphamide in combination with
antithymocyte globulin in affected individuals receiving bone
marrow transplantations from an HLA-identical sibling. For more
information, contact:

Jakob R. Passweg. M.D.

International Bone Marow Transplant Registry

8701 Watertown Plank Road

P.O. Box 26509

Milwaukee, WI 53226

(414) 456-8325

Physicians at Indiana University Medical Center are conducting a
Phase II clinical trial of subcutaneously administered
interleukin-2 in individuals with Myelodysplastic Syndrome.
Eligible individuals must be over the age of 18 years. For more
information, contact:

Micheal S. Gordon, M.D.

Indiana University Medical Center

535 Barnhill Drive, Route 473

Indianapolis, IN 46202-5289

(317) 274-7119

The Hematology Branch at the National Institutes of
Health/National Heart, Lung and Blood Institute (NHLBI) is
conducting clinical research studies on Aplastic Anemia. The
purpose of one of the studies is to compare the use of
antithymocyte globulin combined with cyclosporine versus high dose
cylclophosphmide combined with cyclosporine as a treatment for
Aplastic Anemia. Affected individuals that are eligible for this
study must be 18 years of age or older. Another study is being
conducted on the use of antithymocyte globulin and cyclosporine in
children with Aplastic Anemia (less than 18 years of age). For
more information, individuals may contact:

Wanda Zamani

NIH/Hematology Branch, National Heart, Lung and Blood Institute (NHLBI)

Website: http://www.nhlbi.nih.gov/nhlbi/seekpat/hematol.htm

e-mail: zamaniwe@gwgate.nhlbi.nih.gov

Tel: (301) 402-0764

Fax: (301) 402-3088

For more information, physicians may contact:

Dr. Neal Young, Chief of the Hematology Branch

or Dr. John Barrett, Chief of the Bone Marrow Transplant Unit

NIH/Hematology Branch, National Heart, Lung and Blood Institute (NHLBI)

Website: http://www.nhlbi.nih.gov/nhlbi/seekpat/hematol.htm

Tel: (301) 496-5093

Fax: (301) 496-8396

A phase III clinical trial of antithromocyte globulin,
cyclosporine, corticosteroid, and GCSF with or without stem cell
factor is being subported by the biotechnology company, Amgen. For
information on the study and participating centers contact:

J. Wade Lovelace

Amgen, Inc.

One Amgen Center Drive

Thousand Oaks, CA 91320

Tel: (805) 447-1192

Fax: (805) 480-1330

E-mail: wadel@amgen.com

NORD does not promote, endorse, or encourage participation in any
specific medical research study. This information is presented to
further scientific understanding that could lead to the
prevention, treatment, and/or cure of rare disorders. NORD
recommends that anyone interested in participating in a clinical
research program seek the advice or counsel of his or her own
personal physician(s).

This disease entry is based upon medical information available
through December 1999. Since NORD’s resources are limited, it is
not possible to keep every entry in the Rare Disease Database
completely current and accurate. Please check with the agencies
listed in the Resources section for the most current information
about this disorder.


This information was provided by the National
Organization for Rare Disorders, P.O. Box 8923, New Fairfield, CT
06812-8923, phone: (203) 746-6518, web site: www.rarediseases.org,
e-mail: orphan@rarediseases.org.

For more information on Anemia, Aplastic, please contact:

Anemia & MDS International Foundation, Inc.

P.O. Box 613

Annapolis, MD 21404–0613

e-mail: aamdsoffice@aol.com

Home Page: http://www.aamds-international.org

Heart, Lung and Blood Institute

31 Center Drive MSC 2480

Building 31A Rm 4A16

Bethesda, MD 20892–2480

(301) 592-8573

e-mail: nhlbiinfo@rover.nhlbi.nih.gov

Home Page: http://www.nhlbi.nih.gov/

Anemia Association of Canada

22 Aikenhead Road


Ontario, M9R- 2Z3


(416) 235-0468

e-mail: aplastic@enterprise.ca

Home Page: http://www.aplastic.ualberta.ca

Branch, National Heart, Lung and Blood Institute (NHLBI)

(301) 402-0764

e-mail: zamaniw@nhlbi.nih.gov

Home Page: http://www.nhlbi.nih.gov/nhlbi/seekpat/hematol.htm


Bennett JC & Plum F, eds. Cecil Textbook of Medicine. 20th ed.
Philadelphia, PA: W.B. Saunders Co; 1996:831-37.

Isselbacher KJ, ed. Harrison’s Principles of Internal Medicine.
14th ed. McGraw-Hill, Inc.; 1998:672-75.

Stein, JH ed. Internal Medicine. 4th ed. Mosby-Year Book, Inc.;

Berkow R & Beers M, Eds. The Merck Manual. 17th ed. Merck
Research Laboratories; 1999:862-63.

Behrman RE, ed. Nelson Textbook of Pediatrics. 15th Ed. W.B.
Saunders Company; 1996:599, 1414-15.

Hoffman R, et all, ed. Hematology Basic Principles and Practice.
2nd Ed. Churchill-Livingstone, Inc.; 1995:299-349.

Frank MM, et al, eds. Samter’s Immunologic Diseases. 5th Ed.
Little, Brown and Company; 1995:1478-81.

Tichelli A, et al., Effectiveness of immunosuppressive therapy in
older patients with aplastic anemia. European group for blood and
marrow transplantation severe aplastic anemia working party. Ann
Intern Med. 1999;130:193-201.

Sagmeister A, et al., A restrictive platelet transfusion policy
allowing long-term support of outpatients with severe aplastic
anemia. Blood. 1999;93:3124-6.

Marsh J, et al., 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 (EMBT) severe aplastic anemia working party.
Blood. 1999;93:2191-5.

Young NS, et al., The pathophysiology of acquired aplastic anemia.
N Engl J Med. 1997;336:1365-72.

Kiem Y, et al., Hepatitis-associated aplastic anemia. N Engl J
Med. 1997;337:424-5.

Margolis D, et al., Urelated donor bone marrow transplantation to
treat severe aplastic anemia in children and young adults. British
J Haemaology. 1996;94:65-72.

Issaragrisil S, Brief Report: Transplantation of cord-blood stem
cells into a patient with severe thalassemia. N Engl J Med.

Naser SD, et al., The use of colony-stimulating factors in primary
hematologic disorders. Cancer. 1992;70:921-7.

Frickhofen N, et al., Treatment of aplastic anemia with
antilymphocyte globulin and methylprednisolone with or without
cyclosporine. The German Aplastic Anemia Study Group. N Engl J
Med. 1991;324:1297-304.

The National Organization for Rare Disorders (NORD)
web site, its databases, and the contents thereof are copyrighted
by NORD. No part of the NORD web site, databases, or the contents
may be copied in any way, including but not limited to the
following: electronically downloading, storing in a retrieval
system, or redistributing for any commercial purposes without the
express written permission of NORD. Permission is hereby granted
to print one hard copy of the information on an individual disease
for your personal use, provided that such content is in no way
modified, and that credit for the source (NORD) and NORD’s
copyright notice are included on the printed copy. Any other
electronic reproduction or other printed versions are strictly


Lancet 2000 Nov 4;356(9241):1554-9 Related

Comment in:

  • Lancet. 2000 Nov 4;356(9241):1536-7

High-dose cyclophosphamide in severe aplastic
anaemia: a randomised trial.

Tisdale JF, Dunn DE, Geller N, Plante M, Nunez O, Dunbar CE,
Barrett AJ, Walsh TJ, Rosenfeld SJ, Young NS.

Hematology Branch, National Heart, Lung, and Blood Institute, National
Institutes of Health, Bethesda, MD, USA. johntis@intra.niddk.nih.gov

BACKGROUND: High-dose cyclophosphamide has been proposed as an
alternative immunosuppressive agent for treatment of severe aplastic
anaemia, with a response rate similar to that with regimens containing
antithymocyte globulin (ATG) but neither relapse nor clonal
haematological complications. We undertook a phase III, prospective,
randomised trial to compare response rates to immunosuppression with
either high-dose cyclophosphamide plus cyclosporin or conventional
immunosuppression with ATG plus cyclosporin in previously untreated
patients. METHODS: Between June, 1997, and March, 2000, 31 patients
were enrolled. 15 were assigned cyclophosphamide (1 h intravenous
infusion of 50 mg/kg daily for 4 days) and 16 were assigned ATG (40
mg/kg daily for 4 days); both groups received cyclosporin, initially
at 12 mg/kg daily with adjustment to maintain concentrations at
200-400 microg/L, for 6 months. The primary endpoint was
haematological response (no longer meeting criteria for severe
aplastic anaemia). The trial was terminated prematurely after three
early deaths in the cyclophosphamide group. Analyses were by intention
to treat. FINDINGS: Median follow-up was 21.9 months (range 1-33).
There was excess morbidity in the cyclophosphamide group (invasive
fungal infections, four cyclophosphamide vs no ATG patients; p=0.043)
as well as excess early mortality (three deaths within the first 3
months cyclophosphamide vs no ATG patients; p=0.101). There was no
significant difference at 6 months after treatment in the overall
response rates among evaluable patients (six of 13 [46%]
cyclophosphamide vs nine of 12 [75%] ATG). INTERPRETATION: A longer
period of observation will be necessary to assess the secondary
endpoints of relapse and late clonal complications as well as
disease-free and overall survival. However, cyclophosphamide seems a
dangerous choice for treatment of this disorder, given the good
results achievable with standard therapy.

Publication Types:

  • Clinical trial
  • Randomized controlled trial

PMID: 11075769 [PubMed – indexed for MEDLINE]


Marrow transplants from unrelated donors
for patients with aplastic anemia: minimum effective dose of total body

Deeg HJ, Amylon ID, Harris RE, Collins R, Beatty PG, Feig S, Ramsay N,
Territo M, Khan SP, Pamphilon D, Leis JF, Burdach S, Anasetti C, Hackman
R, Storer B, Mueller B.

Clinical Research Division, Fred Hutchinson Cancer Research Center,
University of Washington School of Medicine, Seattle 98109-1024, USA.

Patients with aplastic anemia who do not have suitably HLA-matched,
related donors generally receive immunosuppressive treatment as first-line
therapy and are considered for transplantation from an unrelated donor
only if they fail to respond to immunosuppressive treatment. In this
setting, rates of transplantation-related morbidity and mortality have
been high. We conducted a prospective study to determine the minimal dose
of total body irradiation (TBI) sufficient to achieve sustained
engraftment when it is used in combination with 3 cycles of 30 mg/kg of
antithymocyte globulin (ATG) and 4 cycles of 50 mg/kg of cyclophosphamide
(CY). We also wanted to determine the tolerability and toxicity of the
regimen. The starting dosage of TBI was 3 x 200 cGy given over 2 days
following CY/ATG. The TBI dose was to be escalated in increments of 200
cGy if graft failure occurred in the absence of prohibitive toxicity, and
de-escalated for toxicity in the absence of graft failure. Twenty-one
female and 29 male patients aged 1.3 to 46.5 years (median age, 14.4
years) underwent transplantation at 14 medical centers. The time interval
from diagnosis to transplantation was 2.8 to 264 months (median, 14.5
months). All patients had been transfused multiple times and all had
received 1 to 11 courses (median, 4 courses) of immunosuppressive
treatment and other modalities of treatment. In 38 cases, the donors were
HLA-A, -B and -DR phenotypically matched with the patients, and, in 12
cases, the donor phenotype differed from that of the recipient by 1 HLA
antigen. Recipients of mismatched transplants were considered separately
for TBI dose modification, and this study is still ongoing. Seven patients
did not tolerate ATG and were prepared with 6 x 200 cGy of TBI plus 120
mg/kg of CY. Of the HLA-matched recipients prepared with CY/ATG/TBI, all
20 who received 3 x 200 or 2 x 200 cGy of TBI achieved engraftment, and 10
are alive. Of the 13 patients who received 1 x 200 cGy of TBI, 1 failed to
engraft, and 8 are alive. Each of 10 patients who received an HLA-nonidentical
transplant achieved engraftment, and 3 of 6 who were given 3 x 200 cGy of
TBI, and 4 of 4 who were given 2 x 200 cGy are alive. Pulmonary toxicity
occurred in 8 of 30 patients who were given 3 x 200 or 2 x 200 cGy of TBI
concurrently with ATG and CY at 200 mg/kg, and in 2 of 13 patients who
received 1 x 200 cGy of TBI, a pattern that suggests a decrease in
toxicity with TBI dose de-escalation. Overall,
the highest probability of survival (73%) was observed among patients who
underwent transplantation within 1 year of diagnosis, compared with
patients who underwent transplantation after a longer period of disease.

In addition, younger patients (aged < or = 20 years) were more likely
to survive than older patients (aged > 20 years). Thus, for patients
with an HLA-matched, unrelated donor, a TBI dose of 200 cGy (in
combination with CY/ATG) was sufficient to allow for engraftment without
inducing prohibitive toxicity. As in previous studies, patient age and
pretransplantation disease duration remain important prognostic factors.

PMID: 11349807 [PubMed – in process]