Transcript Aplastic anemia – lecture 1a

APLASTIC ANEMIA
Aplastic Anemia
• Aplastic anemia is a bone marrow failure
syndrome characterized by peripheral
pancytopenia and marrow hypoplasia.
• Bone marrow failure is a term with a larger
meaning, referring to disorders of the
hematopoietic stem cell which involves
either one cell line or all of the myeloid cell
lines
History of Aplastic anaemia
• Paul Ehrlich (1854-1915) described the first
case of aplastic anaemia in a pregnant
woman who died of marrow failure in1888.
• The term “aplastic anaemia” first used by
Anatole Chauffard in 1904.
Aplastic Anemia – epidemiology
• annual incidence in Europe and US - 2 cases per
million population, but 4 cases in Bangkok 6 in
Thailand and 14 in Japan.
• no racial predisposition exists in the United States;
however, prevalence is increased in the Far East.
• The male-to-female ratio is approximately 1:1.
• Aplastic anemia occurs in all age groups.
– a small peak in incidence in childhood.
– a peak incidence in people aged 20-25 years, and a peak in
people older than 60 years.
Aplastic Anemia - Etiology
• Congenital/inherited (20%)
– Patients usually have dysmorphic features or physical stigmata.
Occasionally, marrow failure may be the initial presenting
feature.
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Fanconi anemia
Dyskeratosis congenita
Shwachman-Diamond syndrome
Familial aplastic anemia
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Acquired:
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Drugs
- Cytotoxic drugs
- Antibiotics
- Chloramphenicol
- Anti-inflammatory
- Anti-convulsant
- Sulphonamides
- 2-3 months usually between exposure and the development of aplastic anemia.
Aplastic Anemia: (Cont.)
• Acquired:
– Radiations
– Chemicals e.g., Benzene and pesticides, chloramphenicol,
phenylbutazone, and gold,
– Viruses:
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Hepatitis A, Non-A and Non-B
Herpes simplex
E-B virus
Parvovirus: Transient
• Important clinically in patients with hemolytic anemias
• 5-10% of cases of AA in the West and 10-20% in the Far East.
• 2-3 months between exposure to the virus and the development of AA.
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Immune: SLE, RA (rheumatoid arthritis)
Pregnancy
Idiopathic: 75%
PNH
Aplastic Anemia - Pathogenesis
Potential mechanisms:
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Absent or defective stem cells (stem cell
failure).
Abnormal marrow micro-environment.
Inhibition by an abnormal clone of
hemopoietic cells.
Abnormal regulatory cells or factors.
Immune
mediated
suppression
of
hematopoiesis.
It is believed that genetic factors play a role.
There is a higher incidence with HLA (11) histo comp.
Antigen. Immune mechanism is involved.
Aplastic Anemia - Pathogenesis (Cont…)
The latest theory is:
• there is an intrinsic derangement of
hemopoietic proliferative capacity, which
is consistent with life.
• the immune mechanism attempt to destroy
the abnormal cells (self cure) and the
clinical course and complications depend
on the balance.
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If the immune mechanism is strong, there will
be severe pancytopenia.
If not, there will be myelodysplasia.
Aplastic Anemia - Forms of disease:
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Inevitable:
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dose related e.g. cytotoxic drugs, ionizing
radiation. The timing, duration of aplasia and
recovery depend on the dose. Recovery is usual
except with whole body irradiation.
Idiosyncratic:
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unpredictable to drugs e.g., anti-inflammatory
antibiotics, anti-epileptic, these agents usually do
not produce marrow failure in the majority of
persons exposed to these agents.
Common Traits To All Various Causes
• Aplasia due to any cause may recover after
immunosuppressive therapy indicating that
immune mechanisms are involved.
• Transition to a clonal disorder of hemopoiesis can
occur in any patient who has recovered bone
marrow function, suggesting that fragility of the
hemopoietic system is common to all forms of
aplasia.
Aplastic Anemia – Clinical Features
• anemia  pallor and/or signs of congestive
heart failure, such as shortness of breath.
• thrombocytopenia

bruising
(eg,
ecchymoses, petechiae) on the skin, gum
bleeding, or nosebleeds.
• neutropenia  fever, cellulitis, pneumonia, or
sepsis
• jaundice and evidence of clinical hepatitis in
subset of patients
Aplastic Anemia – Clinical Features
• adenopathy or organomegaly should
suggest an alternative diagnosis.
• In any case of aplastic anemia, look for
physical stigmata of inherited marrow
failure syndromes such as
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skin pigmentation,
short stature,
microcephaly,
hypogonadism,
mental retardation,
skeletal anomalies.
Aplastic Anemia – investigations
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FBC
Reticulocyte count
Blood film.
B12/folate.
Liver function tests
Virology
Bone marrow aspirate & trephine
PNH screen.
Aplastic Anemia – FBC
• Anemia is common, and red cells appear
morphologically normal. The reticulocyte count
usually is less than 1%.
• Thrombocytopenia, with a paucity of platelets in
the blood smear.
• Agranulocytosis (ie, decrease in all granular
white blood cells, including neutrophils,
eosinophils, and basophils) and a decrease in
monocytes are observed. A relative lymphocytosis
occurs.
• The degree of cytopenia is useful in assessing the
severity of aplastic anemia.
Bone marrow exam
• A bone marrow biopsy is performed in addition to the
aspiration. In aplastic anemia, these specimens are
hypocellular.
• Aspirations alone may appear hypocellular because of
technical reasons (eg, dilution with peripheral blood),
or they may appear hypercellular because of areas of
focal residual hematopoiesis.
• A core biopsy provides 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.
BM Aspiration
BM Biopsy
BM biopsy
hypocellular ,increased fat spaces
APLASTIC ANEMIA – other
investigations
• Hemoglobin electrophoresis may show elevated fetal
hemoglobin.
• Biochemical profile, including evaluation of transaminases,
bilirubin, lactic dehydrogenase, Coombs test, and kidney
function, is useful in evaluating etiology and differential
diagnosis.
• Serologic testing for hepatitis EBV, CMV, and HIV
• Autoimmune disease evaluation for evidence of collagenvascular disease
• The Ham test or sucrose hemolysis test frequently is performed
for excluding PNH.
• Histocompatibility testing should be conducted early to establish
potential related donors, especially in younger patients.
Aplastic Anemia - Criteria for
diagnosis (1)
1. Cytopenia
Hb
<10g/dL
ANC
<1,5 G/L
PL
<100 G/L
2. Bone marrow histology and cytology
- decreased marrow cellularity (< 25%)
- increased fat cells component
- no extensive fibrosis
- no malignancy or storage disease
Aplastic Anemia - Criteria for
diagnosis (2)
3. No preceding treatment with X-ray or
antyproliferative drugs
4. No lymphadenopathy or hepatosplenomegaly
5. No deficiencies or metabolic diseases
6. No evidence of extramedullary hematopoiesis
APLASTIC ANEMIA – differential
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Pancytopenia
Acute Myelogenous Leukemia
Anemia
Aplastic Anemia
Hairy Cell Leukemia
Paroxysmal Nocturnal Hemoglobinuria
Immune pancytopenias in connective tissue
disorders (eg, systemic lupus
erythematosus, refractory anemia)
Causes of pancytopenia
1.Failure of production of blood cells
a) bone marrow infiltration
- acute leukemias
- hairy cell leukemia
- multiple myeloma
- lymphoma
- myelofibrosis
- metastatic carcinoma
b) aplastic anemia
2. Ineffective hematopoesis
- myelodysplastic syndrome
- vit.B12 and folate deficiency
3. Increased destruction of blood cells
- hipersplenism
- autoimmune disorders
- paroxysmal nocturnal hemoglobinuria
4. Myelosuppression after irradiation or antiproliferative drugs
Classification of aplastic anemia
1. Severe aplastic anemia is defined if at last two
of the following criteria are present:
- ANC < 0.5 G/l
- PLT < 20 G/l
- RTC < 1% (20 G/l)
Hypoplastic bone marrow (less than 25%) on
biopsy
2. Very severe aplastic anemia
- criteria as above but ANC < 0.2 G/l
3. Non-severe aplastic anemia.
Evolution of AA - Clinical course 1
• Stable AA
• Pancytopenia remains stable over months to
years.
• Greater the degree of pancytopenia the
worse the prognosis. (see severe aplastic
anaemia)
Evolution of AA - Clinical course 2
• Progressive or fluctuating aplasia.
• Initially small degrees of pancytopenia or
single lineage cytopenia.
• Progressive sometimes following viral
infections.
• Occasionally
single
cytopenia
e.g.
thrombocytopenia becomes true aplastic
anaemia.
Evolution of AA - Clinical course 3.
• Unstable Aplasia.
• Improvement in counts may be associated
with abnormal clones.
• PNH clone in up to 20% of long term
aplastic anaemia.
• Often only detected by lab tests and not
clinically significant.
Aplastic Anemia - Treatment
• Withdrawal of etiological agents.
• Supportive.
• Restoration of marrow activity:
– Bone marrow transplant
– Immunosuppressive treatment
- Prednisolone
- Cyclosporin
- Splenectomy
– Androgens
– Growth factors
- Antilymphocyte glob.
- Anti T cells abs.
APLASTIC ANEMIA – treatment
• Supportiv care
– Transfusion
– Treatment of anemia
– Treatment of bleeding
– Prevention and treatment of infection
HLA identical sibling BMT
• Age <40 years.
• Conditioning with Cyclophosphamide &
antithymocyte globulin, with cyclosporin
and methotrexate.
• Long term overall survival = 80-90%
• Chronic graft versus host disease (GVHD)
remains a problem for 25-40% of patients.
Hematopoietic stem cell transplatation
in severe aplastic anemia
1. Advantages
- correction of hematopoietic defect
- long-term survival: 80% - 90% (HLA-matched sibling donor)
- majority of the patients appear to be cured
2. Restrictions
- age below 40
- suitable donor available in less than 30% (sibling)
- 25-40% risk of GVHD
- 5-15% risk of graft failure in multitransfused patients
- high mortality after MUD-HSCT
- solid tumors (12%)
Immunosuppressive therapy
• Indicated for patients > 40 years
• Patients with no HLA matched sibling
donors.
• Anti-Thymocyte Globulin(ATG) or antilymphocyte globulin (ALG), cyclosporin,
methylprednisolone.
• Best results are for combination therapy.
• Response is slow, 4-12 weeks to see early
improvement.
Immunosuppressive therapy
• Immunosuppressive therapy
– Antithymocyte globulin, equine (Atgam) - 10-20
mg/kg/day for 8-14 days.
– Antithymocyte globulin, rabbit (Thymoglobulin) - 0,75
mg/kg/day for 8 days.
– Cyclosporine (Sandimmune, Neoral) - 1.5-2 mg/kg IV
q12h,
– Methylprednisolone (Medrol, Solu-Medrol) - :5 mg/kg IV
on days 1-8; then tapered using PO 1 mg/kg on days 9-14;
further tapering over days 15-29. Stop after 1 mo except in
evidence of serum sickness.
– Cyclophosphamide (Cytoxan) : 45 mg/kg/d IV for 4 d.
Immunosuppressive therapy 2
• Response rates 60-70%
• Relapses are common and continued
supportive care needed.
• Up to 50% of relapsed patients will respond
to 2nd course of immunosuppressive
therapy.
APLASTIC ANEMIA – treatment
• Other treatments :
– Androgens :
• these agents push the resting hematopoietic stem cells into
cycle, making them more responsive to differentiation by
hematopoietic growth factors and stimulate endogenous
secretion of erythropoietin.
• most are masculinizing and poorly tolerated by females and
children.
• The response rate is limited to approximately 45%, and results
may require 6-10 months of therapy.
– Hematopoietic growth factors - G-CSF and GM-CSF,
may be useful in patients with neutropenia who have
infections, without requiring a WBC transfusion.
Therapy of non-severe aplastic
anemia
1. „Watch and wait”
2. Androgens (?)
3. Supportive care: blood and platelet
transfusion, antibiotics, growth factors
4. Immunosuppressive treatment in selected
patients
APLASTIC ANEMIA – complications
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Infections
Bleeding
Iron overload
Complications of BMT
– Graft versus host disease
– Graft failure
Treatment for adults with acquired severe
aplastic anaemia.
Treatment for adults with acquired non
severe aplastic anaemia
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