2. Introduction
• Refers to pancytopenia in association with
bone marrow hypoplasia/aplasia
• A life-threatening form of bone marrow failure
• If untreated, is associated with very high
mortality
• Most often due to immune injury to
multipotent hematopoietic stem cells.
• Term "aplastic anemia" is a misnomer because
the disorder is characterized by pancytopenia
3.
4.
5. PATHOPHYSIOLOGY
• AA is associated with loss of HSCs and the
resultant decrease in mature blood cells
• Conflicting demands of self-renewal and
differentiation can lead to pancytopenia.
• Pathophysiologic processes that lead to loss of
HSCs and cause AA include:
Autoimmune mechanisms
Direct injury to HSCs (eg, by drugs, chemicals,
irradiation)
Viral infection
Clonal and genetic disorders
6. PATHOPHYSIOLOGY
• It is hypothesized that drugs, chemicals, viruses,
or mutations alter the immunologic appearance
of HSCs and lead to autoimmune destruction
• Cytotoxic lymphocytes and type I cytokines
appear to be proximate effectors of autoimmune
aplasia in AA
• IFN gamma initiates a cytokine cascade
implicated in increased apoptotic death of HSCs
in AA
7. Clonal Evolution
• Development of clonal abnormalities in blood
cells during the course of an individual's life
• AA may coexist with or evolve into other
disorders, such as
Paroxysmal nocturnal hemoglobinuria (PNH)
Myelodysplastic syndromes (MDS)
Acute myeloid leukemia (AML)
• In some cases, immune destruction of the
aberrant HSCs contributes to the cytopenias.
8. CLINICAL MANIFESTATIONS
• Recurrent infections due to neutropenia
• Infections are typically bacterial, including
sepsis, pneumonia, and urinary tract infection
• Invasive fungal infection is a common cause of
death
• Mucosal hemorrhage or menorrhagia due to
thrombocytopenia
• Fatigue and cardiopulmonary findings
associated with progressive anemia
9. CLINICAL MANIFESTATIONS
• Some patients present with hemolytic anemia
or thrombosis that may suggest co-existent
paroxysmal nocturnal hemoglobinuria (PNH)
• Liver, spleen, and lymph nodes are not
typically enlarged and no jaundice in AA
• Other patients are asymptomatic and present
with abnormal blood counts
10. EVALUATION
• Complete blood count suggestive of AA,
should establish the diagnosis of AA
• Seek to identify an underlying cause
• Distinguish it from other categories of
pancytopenia
• Bone marrow biopsy is required to establish
the diagnosis of AA
11. Bone Marrow Examination
• Required to establish the diagnosis of AA and
exclude other causes of pancytopenia
• The biopsy should be performed at a site that
has not suffered prior direct damage (eg,
radiation, trauma, infection)
• Diagnostic criteria, Pancytopenia with a
hypocellular bone marrow in the absence of an
abnormal infiltrate or marrow fibrosis.
12.
13.
14.
15. Specialized Testing
• In all adults with AA, Exclude coexistent
disorders, such as
Paroxysmal nocturnal hemoglobinuria,
Myelodysplastic syndrome
Acute leukemia
• Flow cytometry for assessment of cell surface
CD59 on peripheral blood red blood cells or
neutrophils
• Cytogenetic and molecular testing of bone
marrow
16. Specialized Testing
• In all children with AA we suggest genetic
testing
• To identify inherited genetic abnormalities
• Genetic abnormalities should also be
considered in adults with AA
• Who fail to respond to treatment with anti-
thymocyte globulin (ATG)
17. DIFFERENTIAL DIAGNOSIS
• Megaloblastic anemia
Hypersegmented neutrophils
Macro-ovalocytes on the peripheral blood
smear
Megaloblastic changes in the bone marrow
examination
Low serum levels of vitamin B12 and/or
folate
18. DIFFERENTIAL DIAGNOSIS
Infiltrative disorders
• Bone marrow by fibrosis (eg, myeloproliferative
neoplasms such as primary myelofibrosis)
• Malignancies (eg, MDS, AML, lymphoma,
multiple myeloma, carcinoma)
• Present with myelophthisic changes on the
peripheral blood smear (eg, schistocytes,
nucleated red blood cells)
• And morphologic, cytogenetic, and/or molecular
abnormalities of the bone marrow
19. DIFFERENTIAL DIAGNOSIS
Reversible bone marrow suppression
• Predictable, dose-dependent effects of
cytotoxic chemotherapy or radiation therapy,
• Overwhelming sepsis, or acute viral infection
can cause transient, reversible pancytopenia
with hypoplastic bone marrow
20. DIFFERENTIAL DIAGNOSIS
Hypoplastic MDS
• The hypocellular variant of MDS can be very
difficult to distinguish from AA
• Dysplastic changes in bone marrow and/or
cytogenetic or molecular abnormalities that
are characteristic of MDS
21. Classification of AA Based on Severity
Severe AA
• Bone marrow cellularity <25 percent (or 25 to 50
percent if <30 percent of residual cells are
hematopoietic)
• At least two of the following
Peripheral blood absolute neutrophil count (ANC)
<500/microL (<0.5 X 109/L)
Peripheral blood platelet count <20,000/microL
Peripheral blood reticulocyte count <20,000/microL
22. Classification of AA Based on Severity
Very severe AA
• Diagnosis of very severe aplastic anemia
(vSAA) include the criteria for SAA (above) and
ANC is <200/microL
Non-severe AA — Criteria for non-severe AA :
Hypocellular bone marrow (as described for SAA)
Peripheral blood cytopenias not fulfilling criteria
for SAA or vSAA (see above)
23. Treatment of aplastic anemia in
adults
• Medical fitness
• Performance status (PS) and comorbid
illnesses to determine medical fitness for
intensive therapies
24.
25. ECOG
• In general, patients with ECOG PS >2 are
medically-unfit for
Hematopoietic cell transplantation (HCT)
May not tolerate intensive
immunosuppressive therapy (IST).
27. All patients with SAA/vSAA
• Require prompt treatment decisions and
ongoing supportive care until treatment is
effective.
• Patients with SAA and vSAA are treated
similarly
• Though severity of neutropenia in vSAA
further increases the urgency for initiation of
treatment
28. All patients with MAA
• Follow the patient closely for several weeks to
months to better define the trajectory and
pace of the illness
• When and whom to treat
Red blood cell (RBC) transfusion-
dependence
Persistent, severe neutropenia or
thrombocytopenia
29. Pretreatment Management
• Premedication with Acetaminophen and
Diphenylhydramine before each hATG dose to
reduce infusion reactions
• Prednisone(or methylprednisolone) 1 to 2 mg/kg
daily to prevent serum sickness should begin with
the first dose of hATG
• No beta blockers prior to hATG administration to
allow more effective use of beta adrenergic
agents to support blood pressure, in the event of
a severe anaphylactic reaction to hATG
30. INTENSIVE IMMUNOSUPPRESSIVE
THERAPY
• Lessens the immune injury to multipotent
hematopoietic stem cells in AA by reducing
cytotoxic lymphocytes and associated cytokines
• Triple therapy
• Immunosuppressive agents (horse anti-
thymocyte globulin [hATG]
and cyclosporine [CsA]) together with a bone
marrow stimulating agent (eltrombopag [EPAG]).
31. Administration – hATG
• Given daily for four consecutive days
(beginning on day 1 of triple IST) at a dose of
40 mg/kg intravenously over four hours.
• If infusion reactions are severe, the duration
of each daily infusion can be lengthened to 8
or even 24 hours
32. Adverse effects of hATG
• Infusion reactions, Immediate infusion reactions
to hATG are common and may include fevers to
≥40°C, chills, hypotension or hypertension, third
space sequestration of fluid, and hypersensitivity
rashes
• Serum sickness – Serum sickness is manifest later
than acute infusion toxicities and generally
presents days to weeks after initiation of hATG
with fever, rash, joint pain, malaise, or other
constitutional symptoms
33. Administration Cyclosporine
• Initial dose of 6 mg/kg per day by mouth in
two equal divided doses
• With azole antifungal agents require reduction
in initial dosing to avoid supratherapeutic CsA
levels
• Blood pressure, and serum creatinine should
be monitored
• We generally treat with CsA for 12 months
and initiate a slow taper
36. Outcomes with triple IST
• Triple IST (hATG, CsA, and EPAG) offers the
most favorable balance of outcomes
• More than 90 percent of adults with SAA have
a response to triple IST
• Approximately half of patients have a
complete response (CR)
• Resolution of severe neutropenia and
transfusion-independence generally takes one
to two months
37. Outcomes with Triple IST
• Trials of triple IST have excluded patients with
cytogenetic abnormalities
• Because of concerns that EPAG might
stimulate expansion of an abnormal clone
• Triple IST achieved 97 percent two-year
survival
• The rate of relapse was 15 percent and two-
year cumulative incidence of clonal evolution
was 8 percent
• With median follow-up of 18 months
39. PROGNOSIS
• Current 5- or 10-year survival rates are as high
as 80 to 90 percent, compared with 10 to 20
percent in the 1960s
• Untreated, SAA has a one-year mortality of
over 70 percent
40. REFERENCES
Scheinberg P, Young NS. How I treat acquired aplastic anemia. Blood 2012; 120:1185.
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il 10, 2020).
3. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/050573s035,050574s043,050625s049lbl.pdf (Acc
essed on May 22, 2020).
4. https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/050715s027,050716s028lbl.pdf (Accessed on Apr
il 20, 2020)
5. Update
6. Gill H, Leung GM, Lopes D, Kwong YL. The thrombopoietin mimetics eltrombopag and romiplostim in the treatm
ent of refractory aplastic anaemia. Br J Haematol 2017; 176:991.
7. Lengline E, Drenou B, Peterlin P, et al. Nationwide survey on the use of eltrombopag in patients with severe apla
stic anemia: a report on behalf of the French Reference Center for Aplastic Anemia. Haematologica 2018; 103:2
12.
8. Bacigalupo A. How I treat acquired aplastic anemia. Blood 2017; 129:1428.
9. Scheinberg P. Activity of eltrombopag in severe aplastic anemia. Blood Adv 2018; 2:3054.
10. Scheinberg P, Nunez O, Weinstein B, et al. Activity of alemtuzumab monotherapy in treatment-naive, relapsed, a
nd refractory severe acquired aplastic anemia. Blood 2012; 119:345.
11. Scheinberg P, Nunez O, Wu C, Young NS. Treatment of severe aplastic anaemia with combined immunosuppressi
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