Transcript Aplastic Anemia

Aplastic anemia
Deepa Jeyakumar, MD
Assistant Clinical Professor of
Medicine
10/15/14
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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 ITPgiven IVIG x 1. Did not response to IVIG.
Required daily platelet transfusions.
Bone marrow biopsy
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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.
Diagnosis of Aplastic Anemia
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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.
Severity
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Moderate aplastic anemia
 Marrow cellularity <30%
 Absence of severe pancytopenia
 Depression of at least two of three blood elements below
normal.
Severe
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Bone marrow cellularity <25% or marrow showing <50% normal
with two of three peripheral blood count criteria:
ANC <500
Plt <20k
Retic count <40k
Very Severe
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All of above plus ANC less than 200.
Classification
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Inherited
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Fanconi’s anemia, dyskeratosis congenita, Shwachman-Diamond
Syndrome, Reticular dysgenesis, Amegakaryocytic
thrombocytopenia, familial aplastic anemia, preleukemia
(monosomy 7) and nonhematologic disease (Down, Dubowitz,
Seckel)
Acquired
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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
Differential Diagnosis
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Pancytopenia with hypocellular bone marrow
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- Inherited aplastic anemia
- Hypoplastic AML
Pancytopenia with cellular bone marrow
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Acquired aplastic anemia
Hypoplastic MDS
Primary bone marrow diseases
PNH
Myelophthisis
Hairy cell leukemia
Hypersplenism
Overwhelming infection
Brucellosis
Sarcoidosis
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-MDS
Myelofibrosis
Bone marrow lymphoma
SLE, Sjogren’s disease
Vitamin B12 and folate deficiency
- Alcoholism
Ehrlichiosis
tuberculosis
Hypocellular bone marrow with or without cytopenia
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Q fever
Mycobacteria
Hypothyroidism
- Legionaires disease
- Tuberculosis
- Anorexia nervosa
Hypocellular AML & hypocellular MDS
Epidemiology
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International Aplastic Anemia and
Agranulocytosis Study (IAAAS)
found 2 confirmed cases per one
million people (two PNH units)
Thailand- 4 cases per million
Cumulative survival has increased over
the past few decades
Etiology and Pathogenesis
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Genetic predisposition found in HLADR2.
This correlates to response to
immunosuppressants.
Similar results found in hypoplastic
MDS.
Pathogenesis
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Immune-mediated T-cell destruction
of marrow
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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.
Immune Destruction of Hematopoiesis
Telomere shortening
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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.
Treatment
Treatment
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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.
Intensive Immunosuppression
Clinical Endpoints
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Response defined as transfusion
independence.
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Relapse defined as requirement of
additional immunosuppresants.
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About 50% response rate with horse
ATG.
Happens in 30-40% of patients.
Clonal evolution occurs in 15% of
cases.
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Into MDS, AML, PNH
Improving on ATG & cyclosporine
for first line management of AA?
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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.
Relapsed/Refractory
Aplastic Anemia
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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.
Moderate Aplastic Anemia
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Role for duclizumab, humanized
monoclonal antibody to IL-2
receptor
Role for androgen therapy
HLA-matched sibling
allotransplantation
Risk factors for graft failure
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Heavily transfused
Long time between diagnosis and
transplantation
Alternative Donor Transplant
A 24-year-old man undergoes follow-up
evaluation for treatment of aplastic anemia.
Two of his siblings are HLA-identical matches.
Hemoglobin
Leukocyte count
Platelet count
Reticulocyte count
8.3 g/dL (83 g/L)
(following transfusion of
1 unit of irradiated
packed erythrocytes last
week)
500/µL (0.5 × 109/L)
with 23% neutrophils,
3% band forms, and
71% lymphocytes
26,000/µL (26 × 109/L)
0.2%
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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
Thank You!