This document summarizes the management of aplastic anemia. It discusses the classification, pathogenesis, clinical evaluation, investigations and definitive management including immunosuppressive therapy with antithymocyte globulin and cyclosporine. It also covers supportive management with transfusions, antibiotics and growth factors. Treatment failure options and hematopoietic stem cell transplantation are described. Inherited causes like Fanconi anemia are also summarized.

1. MANAGEMENT OF
APLASTIC ANEMIA
Presentor – Dr. Ritika Khurana
Moderator – Dr. Sunil Gomber

2. APLASTIC ANEMIA
One of the types of bone
marrow failure syndromes
presenting with reduced
hematopoeitic cells of all 3
lineages

3. BM failure syndromes
 Single cytopenia
1. RBC’s
Diamond blackfann syndrome
Congenital dyserythropoetic anemia
Pearson syndrome
Transient erythroblastopenia
Chronic parvovirus B19 infection
2. WBC’s
Shwachman diamond syndrome
Kostmann’s syndrome
Reticular dysgenesis
3. PLATELETS
Congenital amegakaryocytic thrombocytopenia
Thrombocytopenia absent radii syndrome
 Generalized BM failure

4. Classification
Inherited - 30%
Acquired - 70%

5. Inherited
 Fanconi’s Anemia – MC
 Dyskeratosis congenita
 Shwachman diamond syndrome
 Amegakaryocytic Thrombocytopenia
 Diamond blackfann syndrome
 Familial Aplastic Anemias
 Non-hematolog syndromes
 Down’s
 Dubowitz
 Seckel syndrome

6. Acquired
 Idiopathic – MC
 Secondary
• Radiation
• Drugs & chemicals
• Infections – EBV, Hep virus, HIV, CMV
• Immune diseases - Eosinophilic fascitis,
hypoimmunoglobinemia, SLE
• Thymoma
• GVHD
• PNH
• Myelodysplasia

7. Camitta’s Classification
 Mild/Mod(hypoplastic anemia)
ANC 500-1500
Platelet count - 20k-1lac
 Severe aplastic anemia*
ANC < 500
Platelet count - <20k
 Very severe*
ANC < 200
*in addition <25% bone marrow cellularity

8. Pathogenesis
Overproduction of cytokines
 progenitor cells
 shortened telomeres
Immune susceptibility
Poor microenvironment (seed
and soil theory)

9. Clinical Evaluation
History
 Recent illnesses
 Medications
 Exposure to toxins/ Radiation
 Family h/o bleeding disorders,
malignancies, congenital anomalies
O/E
 Vitals
 Ht & Wt
 Congenital anomalies

10. Investigations
 CBC, DLC
 Reticulocyte count
 BM aspiration n biopsy
 Skeletal survey
 Others – LFT, serologic test, flow
cytometry, DEB/ Mitomycin
test(chromosome breakage
analysis), comet assay,
Autoimmune disease evaluation

11. MANAGEMENT
SUPPORTIV
E
DEFINITIV
E
Transfusion
s
Treatment
of infections
Bone Marrow
Transplantation
Immunosupp-ressive
Therapy
Others
1) Alemtuzumab
2) Hematopoietic GF’s
3) Androgens
4) Corticosteroids
5) Anti IL2 –
Daclizumab,

12. Transfusions
 Platelet transfusion if
<10000 or
Visceral bleeding
 Plateletpheresis(Single donor platelets)
to be preferred
 Avoid transfusion from related donor
Role of antibiotics
 No role of prophylactic antibiotics
 Fever or documented infection with
severe neutropenia <500

13. Immunosuppressive therapy
ATG/ALG
Cyclosporin
e
Combined
IST

14. ATG- antithymocyte globulin
 2 types – horse and rabbit ATG
 Immunization of both by human
thoracic duct lymphocytes or
thymocytes
 Mechanism – act against T-lymphocytes,
downregulating
production of IFN gamma, IL2

15. Prerequisites
 Skin testing to be done for
hypersensitivity
 Double lumen central catheter
 Platelet count to be maintained above
20k
 Drugs like ß-blockers to be avoided
 Avoid starting on weekends or late
during day

16. How to administer?
 DOSE –40mg/kg over 4hrs daily for
4days
 Prednisone 1 mg/kg started on day1,
continued for 2 weeks (prophylaxis for
serum sickness)
 Premedications – diphenhydramine,
acetaminophen
 Hydration n supplemental oxygen

17. Side effects n management
 Serum sickness- steroids
 Rash, fever- diphenhydramine,
acetaminophen
 Rigors- mepiridine
 Inc transaminases – regular
monitoring

18. Monitoring response
 Response – within first 3 months
 Earliest response – appearance of
granulocytes and nucleated RBC’s
 Order of rise –
1. RBC’s ( inc HbF)
2. WBC’s
3. Platelets

19. Horse vs Rabbit ATG
 Rabbit ATG more lymphocytotoxic
 Hematologic response to rabbit ATG
(37%) about half that observed with
standard horse ATG (68%),
 Inferior survival noted in the rabbit
ATG arm
Scheinberg P,et al. Horse versus rabbit
antithymocyte globulin in acquired aplastic
anemia. N Engl J Med 2011;365(5):430-438.

20. Cyclosporine
 Fungal cyclic undecapeptide
 Inhibits T-cell - IL-2, IFN-gamma
 Cyclosporine alone lower response rates
n higher risk of disease progression
 Best results seen as combined IST(with
ATG)
 5yr survival rate- 70%
Rosenfeld SJ, et al.Intensive
immunosuppression with antithymocyte
globulin and cyclosporine as treatment for
severe acquired aplastic
anemia. Blood 1995;85(11):3058-3065

21. How to administer?
 Twice daily to maintain trough levels
100-250ng/ml
 Starting dose 15mg/kg/day
 Response takes weeks to months
 Minimum trial period should be 3-6mths
 Ideally ATG×4days n cyclosporine×6-
12mths
 Cyclosporine should be gradually
tapered
Scheinberg P, Horse versus rabbit antithymocyte
globulin in acquired aplastic anemia. N Engl J

22. Adverse effects n
management
 Hypertension – amlodipine
 Hirsutism
 Gingival hyperplasia – azithromycin
 Inc creatinine levels – monitoring and
adjusting dose
 if creat > 2mg/ml – temp cessation n
reintroduction at lower doses
 P.carinii pneumonia- monthly aerosolized
pentamidine
 Dev of Clonal hematopoeitic disorders

23. Definitions
 Complete response- transfusion independence,
neutrophil count >1500/L, platelet count>1lac n
Hb>10g/dl
 Partial remission- transfusion independence,
Hb by atleast 2g/dl n actual value>8,
granulocytes by atleast 500/L, platelets>30k
 No response- continued severe aplastic anemia
 Refractory SAA – severe pancytopenia 6mths
after initiation of IST
Chandra J, et al. Antithymocyte globulin and
cyclosporin in children with acquired aplastic anemia.
Indian J Pediatr. 2008 Mar;75(3):229-33

24. Treatment Failure
 20-40% fail to respond to combined
IST
 Give second course – 77% respond
 Patients failing to respond to 2
courses- unlikely to respond to third
course
 Give trial of androgens, eltromopag, g-csf

25. Role of steroids
 High dose steroids not recommended
as 1st line
 Methylprednisolone in the dose
2mg/kg/day as 0.5mg/kg/dose 6hrly
 Prednisone taper following 8 day
course of IV methylprednisolone over
total of 15 days

26. Role of G-CSF
 G-CSF
increases neutrophil recovery
no increase in trilineage response
Flu like symptoms
Inc risk of clonal evolution
 Seiji Kojima, et al concluded, G-CSF
therapy did not modify long-term
hematopoietic recovery and survival in
patients with severe and very severe
AA

27. Role of eltromopag
 Thrombopoeitin mimetic
 Ideally should be ineffective- already high
levels
 In contrast – 40% responded
(bilineage/trilineage)
 Inc Hb n BM cellularity
 transfusions
 SE – risk of progression to MDS
Young NS. Current concepts in the pathophysiology and
treatment of aplastic anemia. Hematology Am Soc Hematol
Educ Program. 2013;2013:76-81

28. Role of cyclophosphamide
 Used in past
 Efficacy similar to horse ATG
 Fewer relapse rate
 But excessively toxic and inc risk of
fungal infections
 Not recommended anymore
Tisdale JF, et al.High-dose cyclophosphamide
in severe aplastic anaemia: a randomised
trial. Lancet 2000;356(9241):1554-1559

29. Haematopoetic stem cell
transplantation
 <20yrs n HLA matched donors
5yr survival rate 88-97%
 Matched unrelated donors,
unrelated cord blood
survival rate <50%
Gupta V, et al.Impact of age on outcomes after
bone marrow transplantation for acquired
aplastic anemia using HLA matched sibling
donors.Hematologica. 2010;95(12):2119-2125

30. Steps
HLA matching
Preoperative conditioning
regimen
ATG + cyclophosphamide +
cyclosporine
Transplantation

31. Complications
 GVHD
 Secondary solid tumors
 Effect on growth n development
 Effect on endocrine function
 Effect on gonadal function
 Preexisting anti HLA antibodies affect
outcome
Zhu H, et al. Pre-existing anti-HLA antibodies
negatively impact survival of
pediatric aplastic anemia patients undergoing
HSCT. Clin Transplant. 2014 Aug 14

32. Keys to a successful
transplant
 Level of HLA matching
 Good conditioning regimen
 exposure to blood products
 Use of leukocyte free products
 Fludarabine conditioning
 Use of BM stem cell plants rather than
peripheral blood
Schrezenmeier H, et al. Worse outcome and more
chronic GVHD with peripheral blood progenitor
cells than bone marrow in HLA-matched sibling
donor transplants for young patients with severe
acquired aplastic ane- mia. Blood.
2007;110(4):1397-1400.

34. Fanconi’s anemia
 MC inherited cause
 Genes – FANCA, B, C, D
 99% AR, except FANCB – XLR
 Faulty DNA damaged response &
genomic instability
Hematopoeitic failure & cancer
predisposition

35.  Median age – 7yrs
 Usual sequence – thrombocytopenia
granulocytopenia
Macrocytic anemia
 Frequently terminates into MDS / AML
 Diagnosis- chromosome breakage analysis
 BM – hypocellular & fatty replacement with
degree of peripheral pancytopenia

36. Congenital anomalies
 Hyperpigmentation of skin
 Cafe au lait spots
 Short stature
 Skeletal abnormalities
 Male hypogonadism
 Abnormalities of eyes n ears
 Developmental delay
 Renal n cardiac anomalies

38. complications
 Risk of hematological
malignancies – 33%
 Risk of non-hematological
malignancies – 28%
 Limb n skeletal abnormalities –
70%

39. Management
 Mild to moderate cytopenia – monitor
counts every 3-4mths n BMA yearly
 Moderate to severe cytopenia
Androgen therapy – oral
oxymetholone, 2-5mg/kg/day, slowly
tapered
Response seen in 50% within 1-
2mths
Prednisolone 1mg/kg added from
day2

40.  G-CSF daily/ every 2days with
erythropoeitin given sc or iv
3times/week
Increase ANC, platelets & Hb levels
 Allogenic HSCT – only curative
treatment
in children < 10yrs, survival rate >
80%
 Gene therapy – experimental

41. THANK YOU