1.
Aplastic Anemia
Prepared by Kelvin Samike Mmed II
Facilitator: Prof. Antony Oyekunle

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.
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

4.
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

5.
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.

6.
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

7.
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

8.
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

9.
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.

10.
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

11.
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)

12.
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

13.
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

14.
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

15.
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

16.
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

17.
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)

18.
Treatment of aplastic anemia in
adults
• Medical fitness
• Performance status (PS) and comorbid
illnesses to determine medical fitness for
intensive therapies

19.
ECOG
• In general, patients with ECOG PS >2 are
medically-unfit for
 Hematopoietic cell transplantation (HCT)
 May not tolerate intensive
immunosuppressive therapy (IST).

20.
SUPPORTIVE CARE
• Transfusions
• Iron management
• Infection treatment/prevention

21.
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

22.
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

23.
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

24.
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]).

25.
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

26.
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

27.
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

28.
Adverse effects
• Renal insufficiency
• Hypertension
• Magnesium wasting

29.
Administration EPAG
• Begin EPAG 150 mg by mouth once daily
beginning on day 1

30.
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

31.
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

32.
HEMATOPOIETIC CELL
TRANSPLANTATION
• Allogeneic hematopoietic cell transplantation
(HCT) is the only curative therapy for AA

33.
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

34.
REFERENCES
Scheinberg P, Young NS. How I treat acquired aplastic anemia. Blood 2012; 120:1185.
1. Bielory L, Gascon P, Lawley TJ, et al. Human serum sickness: a prospective analysis of 35 patients treated with
equine anti-thymocyte globulin for bone marrow failure. Medicine (Baltimore) 1988; 67:40.
2. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/050715s035,050716s038lbl.pdf (Accessed on Apr
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
on: anti-thymocyte globulin, ciclosporin and mycophenolate mofetil. Br J Haematol 2006; 133:606.