APLASTIC ANEMIA

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APLASTIC ANEMIA
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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

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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.

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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 11.
• 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.

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Aplastic Anemia - Etiology

• Congenital/inherited (20)
• Patients usually have dysmorphic features or
  physical stigmata. Occasionally, marrow failure
  may be the initial presenting feature.
• Fanconi anemia
• Dyskeratosis congenita
• Shwachman-Diamond syndrome
• Familial aplastic anemia
• Acquired
• Drugs
• - Cytotoxic drugs - Antibiotics
• - Chloramphenicol - Anti-inflammatory
• - Anti-convulsant - Sulphonamides
• - 2-3 months usually between exposure and the
  development of aplastic anemia.

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Aplastic Anemia (Cont.)

• Acquired
• Radiations
• Chemicals e.g., Benzene and pesticides,
  chloramphenicol, phenylbutazone, and gold,
• Viruses
• 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.
• Immune SLE, RA (rheumatoid arthritis)
• Pregnancy
• Idiopathic 75
• PNH

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Aplastic Anemia - Pathogenesis

• Potential mechanisms
• 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.

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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.
• If the immune mechanism is strong, there will be
  severe pancytopenia.
• If not, there will be myelodysplasia.

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Aplastic Anemia - Forms of disease

• Inevitable
• 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
• 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.

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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.

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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

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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
• skin pigmentation,
• short stature,
• microcephaly,
• hypogonadism,
• mental retardation,
• skeletal anomalies.

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Aplastic Anemia investigations

• FBC
• Reticulocyte count
• Blood film.
• B12/folate.
• Liver function tests
• Virology
• Bone marrow aspirate trephine
• PNH screen.

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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.

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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.

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BM Aspiration
BM Biopsy
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(No Transcript)
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BM biopsyhypocellular ,increased fat spaces
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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
  collagen-vascular 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.

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Aplastic Anemia - Criteria for diagnosis (1)

• 1. Cytopenia - Hb lt10g/dL
• - ANC lt1,5 G/L
• - PL lt100 G/L
• 2. Bone marrow histology and cytology
• - decreased marrow cellularity (lt 25)
• - increased fat cells component
• - no extensive fibrosis
• - no malignancy or storage disease

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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

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APLASTIC ANEMIA differential

• 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)

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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

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Classification of aplastic anemia

• 1. Severe aplastic anemia is defined if at last
  two of the following criteria are present
• - ANC lt 0.5 G/l
• - PLT lt 20 G/l
• - RTC lt 1 (20 G/l)
• Hypoplastic bone marrow (less than 25) on
  biopsy
• 2. Very severe aplastic anemia
• - criteria as above but ANC lt 0.2 G/l
• 3. Non-severe aplastic anemia.

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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)

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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.

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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.

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Aplastic Anemia - Treatment

• Withdrawal of etiological agents.
• Supportive.
• Restoration of marrow activity
• Bone marrow transplant
• Immunosuppressive treatment
• - Prednisolone - Antilymphocyte glob.
• - Cyclosporin - Anti T cells abs.
• - Splenectomy
• Androgens
• Growth factors

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APLASTIC ANEMIA treatment

• Supportiv care
• Transfusion
• Treatment of anemia
• Treatment of bleeding
• Prevention and treatment of infection

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HLA identical sibling BMT

• Age lt40 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.

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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)

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Immunosuppressive therapy

• Indicated for patients gt 40 years
• Patients with no HLA matched sibling donors.
• Anti-Thymocyte Globulin(ATG) or anti-lymphocyte
  globulin (ALG), cyclosporin, methylprednisolone.
• Best results are for combination therapy.
• Response is slow, 4-12 weeks to see early
  improvement.

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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.

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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.

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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.

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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

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APLASTIC ANEMIA complications

• Infections
• Bleeding
• Iron overload
• Complications of BMT
• Graft versus host disease
• Graft failure

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Treatment for adults with acquired severe
aplastic anaemia.
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Treatment for adults with acquired non severe
aplastic anaemia.