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Aplastic anemia

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Aplastic anemia Deepa Jeyakumar, MD Assistant Clinical Professor of Medicine 10/15/14 – PowerPoint PPT presentation

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Title: Aplastic anemia


1
Aplastic anemia
  • Deepa Jeyakumar, MD
  • Assistant Clinical Professor of Medicine
  • 10/15/14

2
ST
  • Pt is a 43 year old woman who was in her usual
    state of health until 03/16/11 when she presented
    to outside ER with left flank pain and dark urine
    for two days.
  • Found to have hct of 26 with platelet count of
    26k.
  • No hemolysis on labs.
  • Peripheral smear reveals no atypical cells with
    few large platelets. Initially thought to have
    ITP- given IVIG x 1. Did not response to IVIG.
  • Required daily platelet transfusions.

3
Bone marrow biopsy
  • markedly hypocellular marrow with 80 fat.
    Cellularity is composed of entirely maturing
    erythroid elements. Myeloid elements are markedly
    decreased. Occasional segmented forms noted.
    Megakaryocytes rare. Stainable iron increased.
    No ringed sideroblasts. Reticulin focally
    increased. No features of parvovirus seen.
    Several blast forms seen.

4
Diagnosis of Aplastic Anemia
  • Marrow is profoundly hypocellular with decrease
    in all elements.
  • Residual hematopoietic cells are morphologically
    normal.
  • Malignant infiltrates and fibrosis is absent.
  • Hematopoiesis is non-megaloblastic.

5
Severity
  • Moderate aplastic anemia
  • Marrow cellularity lt30
  • Absence of severe pancytopenia
  • Depression of at least two of three blood
    elements below normal.
  • Severe
  • Bone marrow cellularity lt25 or marrow showing
    lt50 normal with two of three peripheral blood
    count criteria
  • ANC lt500
  • Plt lt20k
  • Retic count lt40k
  • Very Severe
  • All of above plus ANC less than 200.

6
Classification
  • Inherited
  • Fanconis anemia, dyskeratosis congenita,
    Shwachman-Diamond Syndrome, Reticular dysgenesis,
    Amegakaryocytic thrombocytopenia, familial
    aplastic anemia, preleukemia (monosomy 7) and
    nonhematologic disease (Down, Dubowitz, Seckel)
  • Acquired
  • Irradiation
  • drugs and chemicals cytotoxic agents, benzene,
    idiosyncratic reaction, chloramphenicol, NSAIDS,
    antiepileptics, Gold
  • viruses EBV, Hepatitis virus (non-A,non-B,
    non-C, non-G), Parvovirus (transient aplastic
    crisis or pure red cell aplasia), HIV
  • Immune diseases eosinophilic fasciitis,
    hyperimmunoglobulinemia, thymoma and thymic
    carcinoma, GvHD in immunodeficiency
  • PNH
  • Pregnancy
  • Idiopathic

7
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8
Differential Diagnosis
  • Pancytopenia with hypocellular bone marrow
  • Acquired aplastic anemia - Inherited aplastic
    anemia
  • Hypoplastic MDS - Hypoplastic AML
  • Pancytopenia with cellular bone marrow
  • Primary bone marrow diseases -MDS
  • PNH - Myelofibrosis
  • Myelophthisis - Bone marrow lymphoma
  • Hairy cell leukemia - SLE, Sjogrens disease
  • Hypersplenism - Vitamin B12 and folate
    deficiency
  • Overwhelming infection - Alcoholism
  • Brucellosis - Ehrlichiosis
  • Sarcoidosis - tuberculosis
  • Hypocellular bone marrow with or without
    cytopenia
  • Q fever - Legionaires disease
  • Mycobacteria - Tuberculosis
  • Hypothyroidism - Anorexia nervosa

9
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10
Hypocellular AML hypocellular MDS
11
Epidemiology
  • International Aplastic Anemia and Agranulocytosis
    Study (IAAAS) found 2 confirmed cases per one
    million people (two PNH units)
  • Thailand- 4 cases per million

12
Cumulative survival has increased over the past
few decades
13
Etiology and Pathogenesis
  • Genetic predisposition found in HLA-DR2.
  • This correlates to response to immunosuppressants.
  • Similar results found in hypoplastic MDS.

14
Pathogenesis
  • Immune-mediated T-cell destruction of marrow
  • Young demonstrated that removal of lymphocytes
    from aplastic bone marrow improved colony number
    in tissue culture and addition of lymphocytes to
    normal marrow inhibited hematopoiesis in vitro.

15
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16
Immune Destruction of Hematopoiesis
17
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18
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19
Telomere shortening
  • Originally thought to be due to stem-cell
    exhaustion.
  • Telomere shortening also found in X-linked form
    of dyskeratosis congenita due to mutations in
    DKCI.
  • Telomere shortening also found in mutations in
    TERC found in AD patients with constitutional
  • Subsequent analysis of patients with acquired
    aplastic anemia found mutations in TERC and TERT.
  • Interestingly, family members of patients who
    share these mutations can have normal blood
    counts but hypocellular marrows, reduced CD34
    counts and poor hematopoietic colony formations
    and short telomeres.
  • Therefore, 1/3 to ½ of patients with aplastic
    anemia have short telomeres but mutations are
    only found in 10 of patients.

20
Treatment
21
Treatment
  • ATG
  • Lymphocyte numbers decreased within the first few
    days of therapy and then return to pretreatment
    levels within a week or so.
  • Appears to be immunomodulatory as well as
    lymphocytotoxic- producing a state of tolerance
    by preferential depletion of activated T cells.
  • Rabbit appears to be more potent that the horse
    formulation.
  • Cyclosporine
  • its selective effects on T-cell function is due
    to direct inhibition on the expression of nuclear
    regulatory proteins, resulting in decreased
    T-cell proliferation and activation.

22
Intensive Immunosuppression
23
Clinical Endpoints
  • Response defined as transfusion independence.
  • About 50 response rate with horse ATG.
  • Relapse defined as requirement of additional
    immunosuppresants.
  • Happens in 30-40 of patients.
  • Clonal evolution occurs in 15 of cases.
  • Into MDS, AML, PNH

24
Improving on ATG cyclosporine for first line
management of AA?
  • Addition of high dose steroids did not improve
    outcomes and just added to toxicity.
  • Addition of G-CSF and GM-CSF did not improve
    outcomes
  • Addition of mycophenolate did not improve
    response rates or outcomes.
  • Sirolimus was equally ineffective.
  • Cyclophosphamide was associated with a higher
    death rate due to prolonged neutropenia.

25
Relapsed/Refractory Aplastic Anemia
  • Rabbit ATG- if patient has not seen it before and
    had a decent response to initial treatment.
  • Alemtuzumab has been shown in the relapsed
    setting to be effective.
  • Cyclophosphamide has a 50 response rate in
    relapsed setting.

26
Moderate Aplastic Anemia
  • Role for duclizumab, humanized monoclonal
    antibody to IL-2 receptor
  • Role for androgen therapy

27
HLA-matched sibling allotransplantation
28
Risk factors for graft failure
  • Heavily transfused
  • Long time between diagnosis and transplantation

29
Alternative Donor Transplant
30
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31
A 24-year-old man undergoes follow-up evaluation
for treatment of aplastic anemia. Two of his
siblings are HLA-identical matches.
Hemoglobin 8.3 g/dL (83 g/L) (following transfusion of 1 unit of irradiated packed erythrocytes last week)
Leukocyte count 500/µL (0.5 109/L) with 23 neutrophils, 3 band forms, and 71 lymphocytes
Platelet count 26,000/µL (26 109/L)
Reticulocyte count 0.2
32
  • Review of the bone marrow biopsy done 2 weeks ago
    confirms the diagnosis of aplastic anemia,
    demonstrating an aplastic bone marrow with normal
    cytogenetics.
  • Which of the following is the most appropriate
    treatment?
  • A Allogeneic hematopoietic stem cell
    transplantation B Antithymocyte globulin,
    corticosteroids, and cyclosporine C Autologous
    hematopoietic stem cell transplantation D
    Corticosteroids E Granulocyte colony-stimulating
    factor

33
  • Thank You!
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