Aplastic anemia management

1. Aplastic Anemia
Dr Nilesh Wasekar
MD Medicine, DM Hematology
Fellowship in BMT
Consultant Hematologist HCG Hospital

2. • Case
• Definition
• Diagnosis
• Risk stratification
• Treatment options
• ATG+CSA
• Indigenous ATG
• Eltrombopeg
• BMT

3. Case
14 years old
girl presented
with easy
fatigability,
gum bleeding
CBC picture:
Hb 4.0 MCV
80 TLC
1500(N22
L78) Plt
4000/mm3
PS was having
: NCNC
Other
investigations
were normal
BMA :
Hypocellular
Bmbx :
Hypoplastic
3
Aplastic anemia

4. Pathophysiology of acquired AA

5. Definition
• Pancytopenia with a hypocellular bone
marrow cellularity <25% (or 25–50% with
<30% residual hematopoietic cells) in the
absence of infiltrate or marrow fibrosis
– with at least two of the following
– Hb <10.0 g/dl, platelet count <50 × 109/l,
neutrophil count <1·5 × 109/l

6. Epidemiology
• The incidence is 2-3 per million per year in
Europe, but higher in East Asia
• The gender ratio is close to 1:1
• There is a biphasic distribution, with peaks at
10-25 years and over 60 years
(Camitta et al, 1975)

7. Etiology : Aplastic Anemia
• IRRADIATION
• DRUGS
Alkylating agents: cyclophosphomide, melphalan, chlorambucil, busulfan
Others: daunorubicin, doxorubicine, carmustine, lomustin,amsacrine, ?
cloramphenicol
• TOXINS:
benzene, glue vapors
• MALIGNANCY
Hairy-cell

8. Etiology : Aplastic Anemia
 CLONAL DISORDERS:
◦ paroxysmal nocturnal hemoglobinuria
 IMMUNE MEDIATED APLASIA:
◦ eosinophilic fasciitis, SLE, GVHD
 INHERITED DISORDERS:
◦ Fanconi’s anemia
 PREGNANCY
 INFECTIONS
• Non-A, non-B, non-C hepatitis, EBV, parvovirus
infection, HIV

9. Indian data
• 2 per million
• Agricultural pesticides:
– Organochlorines e.g. Lindane, Organophosphates,
Pentachlorophenol
– Cutting oils and lubricating agents
– Non-bottled water,
– non-medical needle injury,
– farmers exposed to ducks and geese,
– animal fertilizer
Epidemiology, Pathogenesis and Diagnosis of Aplastic
Anaemia : Sameer R Melinkeri

10. How to investigate

11. The modified Camitta criteria
Severe AA (SAA) cellularity <25% (or 25–50%
with <30% residual haematopoietic cells), plus
at least 2 of:
(i) N <0·5 ×109/l,
(ii) P <20 × 109/l
(iii) R <20 × 109/l
Very Severe AA (VSAA);
•As for SAA but neutrophils
<0·2 × 109/l
Non-severe AA (NSAA);
•AA not fulfilling the criteria for
SAA or VSAA
(Camitta et al, 1975; Bacigalupo et al, 1988

12. Treatment Options

13. Refractory AA

14. ATG

15. TREATMENT OF APLASTIC ANÆMIA BY ANTILYMPHOCYTE GLOBULIN WITH
AND WITHOUT ALLOGENEIC BONEMARROW INFUSIONS B. SPECK
Kantonsspital, Basle, Switzerland E. GLUCKMAN Hôpital Saint-Louis, Paris,
France H. L. HARK J. A. Cohen Institute of Radiopathology and Radiation
Protection J. J. VAN ROOD Bloodbank and Department of
Immunohœmatology University Hospital, Leiden, The Netherlands

16. ATG Types

17. Horse vs Rabbit ATG

18. • Response to a first course of rabbit ATG is
around only 35‒45%, with significantly worse
OS
• The 6-month response rate to a first course of
horse ATG is around 70%

19. MOA
T-cell depletion
Modulation of
key cell surface
molecules
leukocyte/endo
thelium
interactions
Apoptosis in B-
cell
Interference
with dendritic
cell function

20. ATG
Admini
stration
of ATG
Antithym
ocyte
globulin
must be
given as
an in-
patient
Prior to
starting
ATG:
The patient
should be
clinically stable
and ideally
afebrile
Platelet count
increment studies
should be
performed to
exclude platelet
refractoriness
Prophylactic antiviral,
antibiotic and antifungal
drugs should be administered
according to local policy
For
patient
s aged
>60 yea
rs,
careful
assess
ment of
co-
morbidi
ties

21. The dose of
horse ATG
(ATGAM) is
40 mg/kg/d
for 4 d
It is given as
an
intravenous
infusion over
12-18 h
Due to the risk
of
anaphylaxis, a
‘test’ dose
must be given
the first
100 ml of the
first day
infusion is
given over 1 h
ATG should be
given through
a double
lumen
Hickman or
other central
venous
catheter
(recent survey of the EBMT SAA Working Party,
unpublished data May 2012),

22. Each dose of ATG preceded with
intravenous mps 1 mg/kg, Avil,
to keep the platelet count >20–30 × 109/l
Infections should be treated as per FN
fluid balance is important
Prednisolone is started on the day after
ATG is completed
(Marsh et al, 2009; Scheinberg & Young, 2012)

23. Side effects of ATG
• Immediate infusion related and anaphylaxis
• Serum sickness most commonly with
arthralgia, myalgia, rash and fever
• Treated with steroids
• Extra platelet transfusions

24. Gcsf
• There is no indication for using G-CSF with
ATG + CSA, as prospective randomized studies
have shown that daily G-CSF given for
3 months after ATG does not improve
response or overall survival (OS)
(Tichelli et al, 2011)

25. Cyclosporine
at a dose
of
5 mg/kg/d
to
achieve
trough blood
levels of
100–200 μg/l
CSA should be
continued
whilst the
blood count
continues to
rise
A slow tapering
of the drug
(25 mg every
2‒3 months)
12 months of
therapy
(Dufour et al, 2013)

26. outcomes
• Response to ATG is delayed, starting after an
average of 3‒4 months
• The 6-month response rate to a first course of
horse ATG is around 70%
• Five-year OS is age-dependent:
– 100% for age <20 years,
– 92% for 20–40 years,
– 71% for 40–60 years and
– 56% for >60 years

27. • For NSAA, ATG + CSA results in significantly
higher response rates, 74% versus 46% (and
better event-free survival), compared to CSA
alone
(Scheinberg et al, 2011; Marsh et al, 2012;
Scheinberg & Young, 2012)

28. Long Term Effects
• Relapse Rate 35%
• Clonal evolution to MDS/acute myeloid
leukemia is 15%
• Haemolytic PNH in 10%
(Rosenfeld et al, 2003; Scheinberg &
Young, 2012).

29. Response to ATG predictors
Young age NSAA
ARC >25 × 109/l and
ALC >1·0 × 109/l
trisomy 8 or
del(13q)
The presence of a
PNH clone
longer telomeres
35% for refractory
AA

30. Front line therapy for AA

31. Indigenous ATG

32. Eltrombopeg in Aplastic Anemia

33. The rate of complete
response at 6 months
was 33% in cohort 1, 26%
in cohort 2, and 58% in
cohort 3
The overall response
rates at 6 months were
80%, 87%, and 94%,
respectively
historical cohort, rate of
complete response was
10% and the overall
response rate was 66%
At a median follow-up of
2 years, the survival rate
was 97%
40% RR as a single agent
Rates of relapse and
clonal evolution were
similar to historical
experience

34. Why do patients fail to respond after
immune suppressive therapy?
1. The cytotoxic T cells persist and the immune
attack continues
2. The marrow compartment is too damaged to
recover
3. A new defect is present (MDS)
4. Unrecognized inherited marrow defect

35. Copyright ©2006 American Society of Hematology. Copyright restrictions may apply.
Marsh, J. Hematology 2006;2006:78-85
Treatment for adults with acquired non severe aplastic
anaemia.

36. Danazol
• 30% RR
• Dose : can be given upto 800mg/day
• Problems : abnormalities of LFT
• Useful in Telomeropathy and fancony’s anemia
• Triple oral(CSA+DANAZOL+Eltrombopeg) can
be tried in elderly who are not fit for ATG

37. HSCT
Conditioning
Donor
Stem cell
source
GVHD
Prophylaxis
ABO
mismatch
CMV Status
Long term
follow up

38. MSD
Institutio
n/study
Years of
study
N Age, y
(median
in y)
Graft
rejection
/failure,
%
Acute
GVHD,*%
Chronic
GVHD, %
Actuarial
survival,
%
IBMTR92 1988-
1992
471 20 (1-51) 16 19 32 66 at 5 y
Vienna93 1982-
1996
20 25 (17-
37)
0 26 53 95 at 15
y
EBMT94 1991-
1998
71 19 (4-46) 3 30 35 86 at 5 y
Seoul95 1990-
1999
22 22 (14-
43)
5 10 33 95 at 5 y
Seoul96 1990-
2001
64 28 (14-
43)
18 31 19 79 at 6 y
Hamburg
97
1990-
2001
21 25 (7-43) 5 5 5 86 at 5 y

39. Alternative Donor
Study Year of
publicat
ion
N Donor
source,
N
Conditi
oning
Age, y,
median
(range)
Acute
GVHD,*
%
Chronic
GVHD,
%
Survival
, %
Nagoya
111
2001 15 MUD:
11;
MMUD:
4
Cy/ATG/
TBI
11 (3-
19)
33 13 100 at 4
y
Great
Britain1
12
2001 8 MUD:
7;
MMUD:
1
Cy/CP/T
BI
7 (0-10) 25 0 100 at 3
y
Japan
Marrow
2002 154 MUD:
79;
MMUD:
75
Cy ± TBI
or LFI;
Cy/ATG
± TBI or
LFI
17 (1-
46)
29 30 56 at 5
y

40. Elderly AA

41. Thank
You