APLASTIC ANAEMIA-CAUSES,TREATMENT

1. Aplastic anemia
Anoop.K.R, MD
Assistant Clinical Professor of
Medicine

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 <30%
 Absence of severe pancytopenia
 Depression of at least two of three blood elements below
normal.
 Severe
o Bone marrow cellularity <25% or marrow showing <50% normal
with two of three peripheral blood count criteria:
o ANC <500
 Plt <20k
 Retic count <40k
 Very Severe
 All of above plus ANC less than 200.

6. Classification
 Inherited
 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
 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

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, Sjogren’s 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

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.

17. 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.

18. Treatment

19. 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.

20. 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

21. 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.

22. 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.

23. Moderate Aplastic Anemia
 Role for duclizumab, humanized
monoclonal antibody to IL-2
receptor
 Role for androgen therapy

24. HSCT
 Definitive therapy for several malignant
and non malignant disorders
-autologous : stem cells harvested from
the patient
-allogeneic : stem cells collected from a
donor

25. ALLOGENEIC HSCT
 Ideal donor is a HLA-identical sibling
 Even minor histocompatibility loci
variations can cause graft rejection/graft
versus host disease
 ABO blood group compatibility not
essential
 If HSCT is successful,blood group of
recipient changes to that of donor

26. - myeloablative -> high doses
chemotherapy administered to
eradicate malignant cells,to clear
space for growth of donor stem
cells,to suppress host immune
response
- non myeloablative -> donor T cells
are used to eradicate both
malignant and non malignant cells
of host origin

27.  Harvesting :
-Under GA/spinal.
-Repeated aspiration done.
-From posterior iliac crests.
-Minimum no.of marrow cells required is 1-3 X
10 power 8 cells/kg of recipient’s body
weight.

28.  Engraftment :
-These donor marrow cells are
transfused through peripheral veins.
-Enter into host marrow space and
start engrafting.
-2-3 weeks for engraftment to occur.

29. -Prone to bacterial and fungal infections.
-Protective isolation required during this period.
-Require multiple red cell and platelet
transfusions for the thrombocytopenia.
-Engraftment considered successful when
peripheral ANC > 500/mm3 on three
successive days.
 Risk of GVHD after transplant -> irradiation
prior to transplant to inactivate donor
lymphocytes

30. GRAFT VERSUS HOST DISEASE
 Occurs in allogeneic stem cell
transplant.
 Acute / chronic .
 Acute :
Occurs within the first 3 months after
transplant
Classically affects only skin,gut and
liver
(skin lesions,diarrhoea,jaundice)
Accompanied by fever

31.  Chronic :
Develops later than 100 days after the
transplant.
De novo / follows acute GVHD .
Limited/extensive .
Resembles scleroderma( skin rash,sicca
complex,sclerosing bronchiolitis,hepatic
dysfunction ).
Mortality of 20-40% .
Mx – immunosuppressive agents.

32. Thank You!