Aplastic Anemia Facts and Statistics
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eMedicine
Journal >
Medicine,
Ob/Gyn, Psychiatry, and Surgery >
Hematology
Aplastic Anemia
Synonyms, Key Words, and Related Terms: progressive
hypocythemia, aregeneratory anemia, aleukia hemorrhagica,
panmyelophthisis, hypoplastic anemia, toxic paralytic anemia |
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AUTHOR
INFORMATION |
Section
1 of 11
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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
eMedicine Journal, June 19 2001, Volume 2, Number
6
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INTRODUCTION |
Section
2 of 11
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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.
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.
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- Anemia may manifest as pallor, headache, palpitations,
dyspnea, fatigue, or foot swelling.
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- Thrombocytopenia may present as mucosal and gingival
bleeding or petechial rashes.
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- 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.
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- 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.
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- 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%)
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- Patients usually have dysmorphic features or physical
stigmata. Occasionally, marrow failure may be the initial
presenting feature.
- Fanconi anemia
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- Cartilage hair hypoplasia
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- Amegakaryocytic thrombocytopenia (TAR syndrome)
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- Shwachman-Diamond syndrome
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- Diamond-Blackfan syndrome
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- Infectious causes such as hepatitis viruses, Ebstein-Barr
virus (EBV), HIV, parvovirus, and mycobacterial infections
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- Toxic exposure to radiation and chemicals such as benzene
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- 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.
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- 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.
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- Transfusional graft-versus-host disease
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- Orthotopic liver transplantation for fulminant hepatitis
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DIFFERENTIALS |
Section
4 of 11
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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
Lab Studies:
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- 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.
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- 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.
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- 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.
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- A leukemic process may show evidence of blasts on the
peripheral smear.
- Bone marrow aspiration and biopsy
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- 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.
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- 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.
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- Patients with leukemia and metastatic cancers also may be
diagnosed with bone marrow examination.
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- 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.
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- 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.
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- Bone marrow culture is useful in diagnosing mycobacterial
and viral infections. However, the yield generally is low.
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- 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.
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- Biochemical profile including evaluation of transaminases,
bilirubin, lactic dehydrogenase, Coombs test, and kidney
function is useful in evaluating etiology and differential
diagnosis.
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- Serologic testing for hepatitis and other viral entities
such as EBV, CMV, and HIV
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- Autoimmune disease evaluation for evidence of
collagen-vascular disease
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- 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.
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- 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.
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- 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
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
biopsy.
Staging: Based on International Aplastic Anemia
Study Group (Camitta et al)
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- Neutrophils - Less than 0.5x10'9/L
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- Platelets - Less than 20x10'9/L
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- Reticulocytes - Less than 1% (corrected) (percentage of
actual Hct/normal Hct)
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- 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.
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TREATMENT |
Section
6 of 11
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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:
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- Any activity that increases the risk of trauma during
periods of thrombocytopenia
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- Risk of community-acquired infections during periods of
neutropenia
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MEDICATION |
Section
7 of 11
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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
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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
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| Pediatric Dose |
Administer as in adults
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| 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
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| 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
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| Pregnancy |
C - Safety for use during
pregnancy has not been established.
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| 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
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Drug Name
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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.
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| 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
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| Contraindications |
Documented
hypersensitivity; viral, fungal or tubercular skin
infections
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| 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
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| Pregnancy |
C - Safety for use during
pregnancy has not been established.
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| Precautions |
Hyperglycemia, edema,
osteonecrosis, peptic ulcer disease, hypokalemia,
osteoporosis, euphoria, psychosis, growth suppression,
myopathy, and infections are possible complications of
glucocorticoid use
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Drug Name
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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
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| Pediatric Dose |
Administer as in adults
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| Contraindications |
Documented
hypersensitivity; unremitting leukopenia and/or
thrombocytopenia
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| Interactions |
None reported
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| Pregnancy |
C - Safety for use during
pregnancy has not been established.
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| 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
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Drug Name
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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
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| Pediatric Dose |
Administer as in adults
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| Contraindications |
Documented
hypersensitivity; severely depressed bone marrow function
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| 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
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| Pregnancy |
D - Unsafe in pregnancy
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| Precautions |
Regularly examine
hematologic profile (particularly neutrophils and platelets)
to monitor for hematopoietic suppression; regularly examine
urine for RBCs, which may precede hemorrhagic cystitis
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Drug Name
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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
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| Pediatric Dose |
Not established
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| Contraindications |
Documented
hypersensitivity
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| Interactions |
None reported
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| Pregnancy |
C - Safety for use during
pregnancy has not been established.
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| 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
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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
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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
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| Pediatric Dose |
Not established; 5
mcg/kg/d SC has been used in some studies
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| Contraindications |
Documented
hypersensitivity
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| Interactions |
None reported
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| Pregnancy |
C - Safety for use during
pregnancy has not been established.
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| 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
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Drug Name
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Filgrastim (Neupogen)-
Granulocyte colony stimulating factor that activates and
stimulates production, maturation, migration, and
cytotoxicity of neutrophils.
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| Adult Dose |
5 mcg/kg/d SC until ANC
has reached 5000/cc
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| Pediatric Dose |
5-10 mcg/kg/d SC
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| Contraindications |
Documented
hypersensitivity
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| 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
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| Pregnancy |
C - Safety for use during
pregnancy has not been established.
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| Precautions |
Risk of developing
myelodysplastic syndrome or acute myeloid leukemia in
certain patients; leukocytosis; possible tumor growth
|
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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.
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
basis.
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.
Transfer:
- 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
years.
Complications:
- Graft-versus-host disease
|
|
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
 |
 |
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:
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| Medicine is a
constantly changing science and not all therapies are
clearly established. New research changes drug and treatment
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In particular, all drug doses, indications, and
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|
eMedicine Journal, June 19 2001, Volume 2, Number
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© Copyright 2001, eMedicine.com, Inc.
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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
Registry to keep track of patients for statistical analysis.
Myelodysplastic
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
Registry 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 aplastic
anemia 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
21404-0613
800.747.2820
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 me
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 scan
them and send them off to you. All BMTs are from HLA identical siblings.
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
therapy 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
with1988-1997. 1970-75 shows about a 50% survival
rate up to about 15 years. This then drops off to
45% 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 years.
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 Aplastic
Anemia for Allogeneic Marrow Transplantations: The Experience in
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 used
now on ages between 2 and 59. It can be found at
http://mmserver.cjp.com/gems/bbmt/7.1.Storb.pdf
What I found interesting about this report is
that it deals with 93 cases and gives the
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 very
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 same...infections
that got out of control.
|
|
|
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.
Conclusion
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
J.
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
time.
- ·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.
Nancy
B. Davis
EDITOR:
ANNE LeMAISTRE, M.D.
CREATED: 6/24/94, LAST MODIFIED: 4/24/96, UT DPALM MEDIC, copyright
1994-96 |
apoptosis
<cell
biology> Programmed
cell death as signalled by the nuclei in normally functioning human
and animal cells
when age or state
of cell health
and condition
dictates.
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
responses 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
mutant, bcl.
(18 Nov 1997)
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apoplectical,
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© 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 PubMed.
Tisdale JF, et al. "High-dose cyclophosphamide in severe aplastic
anemia: a randomized trial." The
Lancet, Nov 4, 2000. Vol 356, no 9241, p 1554.
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