16

supplement to Journal of the association of physicians of india Published on 1st of every month 1st march, 2015

Immunosuppressive Therapy for Aplastic Anaemia

S Damodar*

Abstract
Immunosuppressive therapy is the standard of care in aplastic anaemia in younger patients who do
not have a matched sibling donor, and also in adults and older patients. Hence, a large population of
patients with aplastic anaemia undergo this treatment. In patients who have responded to the first course
of ATG, and have had a relapse, a second course of ATG can be administered with reasonable response
rates. Response rates to first course of ATG vary from 50-85% in both children and adult. Indian data also
suggests similar response rates.

Introduction longer, preventing subsequent relapses.

A number of immunosuppressive agents

T herapy for aplastic anaemia

( A A) e s s e n t i a l l y c o n s i s t s o f 3
modalities stem cell transplant (SCT),
immunosuppressive therapy (IST) and
supportive care only. Supportive care is
the bare minimum, which is the common
factor to any treatment. We will discuss
the option of immunosuppressive therapy
in relation to its feasibility in our country.
History of IST for Aplastic
Anemia
The first reports of IST working in
AA came from patients who received
conditioning therapy for stem cell
transplant but failed donor engraftment
and had autologous recovery of
hematopoiesis. 1,2 This leads to the theory
that immunosuppression itself may
be sufficient in some patients to allow
hematopoietic recovery. Subsequent
studies then showed that the infusion of
Anti-lymphocyte globulin (ALG) alone
lead to hematopoietic recovery and
based on the results of a prospective
randomised trial,3 IST became the
standard of care for AA patients in whom
transplant was not a feasible option. This
study clearly demonstrated that anti-
thymocyte globulin (ATG) was superior
to best supportive care (response rates
were 52% and 0% respectively with an
additional 50% response after cross-
over ), even if a complete normalisation
of blood counts was not achieved in
many responders. Response rates using
ATG or ALG ranged between 30% and
70% in larger series from other groups,
Dept of Haematology,
* which also pointed out the risk of
Narayana Health city / late treatment failure due to disease
Mazumdar Shaw Cancer relapse. 4,5 Thus, the subsequent aim for
Centre, 258/A Bommasandra investigators was to increase the response
industrial area, Anekal Taluk, rate and sustain such responses for
Bangalore-560099
were initially combined with ATG or
ALG, including corticosteroids (i.e.
m e t h yl p r e d n i s o l o n e ) , 6 a n d r o g e n s 7 , 8
and Cyclosporin A (CyA). Only CyA, a
calcineurin inhibitor (CNI) that impairs
i n t e r l e u k i n ( I L) - 2 - d e p e n d e n t T c e l l
activation and differentiation, has proven
effective in increasing the response rate,
as initially demonstrated by the German
Aplastic Anaemia Group in a randomised
trial 9 . In fact, the addition of CyA to
ATG and high dose steroids (utilised as
prophylaxis of serum-sickness) increased
the 6-month overall response rate from
46% to 70% in all AA patients (from 31% to
65% in severe or very severe forms only),
possibly impacting long term survival
( e ve n i f n o s t a t i s t i c a l l y s i g n i f i c a n t
difference was shown in this initial
cohort). This study leads us to the present
day; in fact, based on these results, ATG
+ CyA has been the most utilised IST for
AA patients in the past two decades in
Western countries. Unfortunately, the
access to such treatment still represents a
problem in developing countries, mainly
due to economic reasons. 10
When and Whom to Treat
Patients who are transfusion
independent or moderate aplastic
anaemia, observation would be the
appropriate treatment. Many patients
with AA may present stable blood counts
for years, but pancytopenia may worsen
over time in some.11 Patients who progress
to severe pancytopenia and meet the
criteria for SAA or become transfusion-
dependent, can then be treated according
to current algorithms (Figure 1). Elderly,
feeble, or patients experiencing severe
comorbidities might not benefit from
more aggressive treatment approaches,
supplement to Journal of the association of physicians of india Published on 1st of every month 1st march, 2015 17
< 40 years
Sibling donor No sibling donor
H -ATG + CSA
No response Response
MUD 10/10 NO MUD
relapse
2nd IST
Failure response
3RD IST
9/10 MUD
HSCT
HAPLO
CORD relapse
HSCT-haematopoietic stem cell transplant, MUD- matched unrelated donor, EXP experimental therapy, IST immunosuppressive therapy,
BST best supportive care
Fig. 1 : Algorithm for approach to aplastic Anaemia
particularly if they are not bleeding and have
neutrophil counts (generally between >200 -400/L) that
defend them from serious infections.
Standard Immunosuppression
S i n c e t h e e a r l y 1 9 9 0 s , AT G + C y A h a s b e e n
considered the standard IST for AA patients, with
an expected 5060% probability of response and
60% overall survival at 1 year. 12-14 A heterogeneous
definition of clinical response may account for
differences in response rates in distinct studies, thus
the use of common response criteria is encouraged, 15
even more so because such criteria clearly predict
the long-term survival of AA patients. 16 Most studies
reported a response rate [complete response (CR)
+ partial response (PR)] ranging from 50% to 70%,
without any improvement in the past two decades.
However, most recent studies have shown improved
overall survival (above 80% at 1 year ), regardless of
the initial response to IST, 16-18 probably due to better
supportive care and salvage treatment (mainly HSCT).
ATG Preparations
ATG is a heterologous anti-serum obtained by
injecting human lymphocytes in animals; various
ATG preparations exist, which differ in stimulating
antigens (peripheral lymphocytes, thymocytes or even
T cell lines), and/or in the host animal (either horse
or rabbit). In the last two decades physicians have
utilised any commercially available ATG preparation
without distinction. Most available data from large
randomised clinical trials refer to polyclonal ATGs
obtained from horse (h), which have to be considered
the gold standard for AA treatment. Of note, U.S.
and Japanese investigators utilised hATG (40 mg/kg
per day for 4 days, ATGAM; Pharmacia and Upjohn,
New York, NY, U.S.), 16,18 which is different from the
hATG preparation used in Europe (15 mg/ kg per day
for 5 days, Lymphoglobuline; Genzyme, Cambridge,
MA, U.S.; Fresenius Biotech, Munich, Germany) 19 .
Thus, both preparations can be considered equivalent
as standard IST for AA; however, Lymphoglobuline
is no longer available. Alternative polyclonal ATGs
40-60 years > 60 years
H-ATG +CSA H-ATG + CSA
No response response No response response
Sibling donor No donor
relapse relapse
2nd IST 2nd IST
failure Response failure response
3rd IST
MUD Sibling donor EXP
HSCT
HALPLO HSCT BST Relapse
CORD relapse
BST
may be obtained from rabbits (r ); two rATGs are
currently available (Thymoglobuline, Genzyme; ATG-
Fresenius), but to date the clinical results with these
agents are less robust for the lack of large randomised
trials. However, hATG (ATGAM) is the recommended
first line IST for patients ineligible for HLA identical
sibling haemopoietic stem cell transplantation (HSCT)
as stated by the British Committee for Standards
in Haematology (BCSH) guidance following the
results obtained from a prospective randomised trial
comparing hATG versus rATG for the treatment of
AA. 20 rATG is more immunosuppressive than hATG
but does not improve haematological recovery as
compared to hATG. rATG is used successfully to
salvage patients with refractory or relapsed SAA
following initial hATG. 11
Immunosuppression Administration
ATG
During the administration of ATG, referral to
hospitals with experience in treating SAA or enrolment
into research trials should be encouraged, owing to
the unfamiliarity of the administration of polyclonal
antibodies and its immediate toxicities, such as ATG,
amongst inexperienced nurses and physicians. To
test for hypersensitivity to horse serum an ATG skin
test should be performed. 11 Furthermore, ease of drug
delivery and transfusions can be improved with the
use of a double lumen central line. Scheinberg and
Young recommend maintaining platelets at more
than 20000/L during the ATG administration period. 11
In cases of platelet refractoriness, they recommend
testing for alloantibodies to determine the need for
best matched platelet products and using universal
filtration of blood products to prevent alloantibody
formation. While there is no formal recommendation
regarding the use of irradiated products after hATG
in SAA patients, their practice has been to apply
universal irradiation in their protocols, in accordance
with recommendations from a European study
survey. 21 Establishing responsiveness to antibiotic
therapy for bacterial infections is preferred, even
though patients need not be free of infection before
18 supplement to Journal of the association of physicians of india Published on 1st of every month 1st march, 2015
starting ATG. 11 However, it is important to note
that prolonged attempts to clear fungal infections
or extensive bacterial infections can defer definitive
IST or HSCT therapies. b-blockers may be withheld
before ATG to evade suppression of physiologic
compensatory responses to anaphylaxis. It is also
advisable to not initiate ATG late in the day or on
weekends when hospitals may be understaffed. 11
The normal daily dose of ATG is 40mg/kg over
4 hours, for 4 days. Prophylactic treatment for
serum sickness may be initiated on day 1 with
Prednisone 1 mg/kg, which may be continued
for 2 weeks. Conventional premedication prior
to every ATG dose involves acetaminophen and
diphenhydramine. Furthermore, symptomatic
management of common infusion reactions may
comprise of meperidine (rigors), acetaminophen
( f e ve r s ) , d i p h e n h y d r a m i n e ( r a s h ) , i n t r a ve n o u s
hydration (hypotension), and supplemental oxygen
(hypoxaemia). 11 Haemodynamic and/or respiratory
compromise can result in admittances to the intensive
care unit, vasopressor support, and even, although
infrequently, intubation. Under life-threatening
circumstances, it is recommended that the ATG
infusion is slowed or briefly stopped till severe signs
and symptoms recede. ATG may be reinitiated at a
normal or slower infusion rate in a monitored setting,
occasionally over a 24 hour period, subject to the
severity of the reactions. ATG may be infused even
if patients experience mild to moderate elevation in
transaminases, and increased liver enzymes tend to
normalise over several days. Management of infusion
related toxicities should not comprise of switching
ATG formulations, for example, from horse to rabbit.
Moreover, to manage rising creatinine, CsA can
be withheld in the short term until renal function
recovers. 11
Cyclosporine
CsA may be initiated on day 1 at a daily dose of 10
mg/kg (15 mg/kg per day in children) to a target trough
level between 200 and 400 ng/mL. 22 Patient frequently
develop hypertension during CsA treatment, and
management with amlodipine is recommended owing
to minimal overlap with CsA related toxicities. A short
course of azithromycin is recommended to improve
gingival hyperplasia. 23 It is important to note that
calcium channel blockers have been associated with
worsening gingival hyperplasia when combined
with CsA. 24 CsA may be continued despite modest
increases in creatinine, with careful monitoring of
the patients renal function and dose modifications
to attain the desired CsA levels. Sustained CsA use
requires dose adjustment of the CsA to the lower end
of the therapeutic range, optimized blood pressure
control, adequate hydration and the avoidance of other
nephrotoxic agents to allow for improved tolerability.
Temporary cessation of CsA is advised in patients with
severe compromise of kidney function from baseline
(creatinine >2mg/ mL). Low doses of CsA may be
reintroduced at a later stage, with gradual increases
proportionate to the patients tolerability. 11
G-CSF
Use of G-CSF in combination with immunosuppression
has not shown any benefits in terms of hematologic
response or survival in SAA patients. 25-32 Hence it
is not recommended to use with ATG owing to the
lack of benefit and the theoretical risk of harmful
side-effects. 11 In fact, some retrospective studies have
reported an increased risk of clonal evolution with
G-CSF use, 33-35 but this remains to be confirmed. 36
The decision to try to improve neutrophil with G-CSF
in select patients who are actively infected or those
that experience persistent severe neutropenia (< 200/
uL) should be based on clinical grounds. However,
if there is no significant response, reassessment and
discontinuation after no more than a few days or weeks
is advised. 11
Antimicrobial prophylaxis
As prophylaxis for Pneumocystis carinii infections
while patients are on therapeutic doses of CsA,
monthly aerosolised pentamidine is suggested. The
basis of this regimen follows the observation that
several cases of P carinii pneumonia were reported by
Scheinberg and Young at their institution in the late
1980s in AA patients who were treated with horse ATG
and CsA. 11 Treatment with dapsone or atovaquone
may be used when aerosolised pentamidine cannot
be tolerated or in very young children. However,
sulfa drugs should be avoided because of their
myelosuppressive properties. 11 While antibacterial,
antiviral, and antifungal prophylaxes are not routinely
administered with standard horse ATG/CsA, they have
been used in the context of investigational regimens
that are more immunosuppressive. 11
Response and Follow-Up
Most AA patients achieve some clinical benefit
from IST, but the quality of response is heterogeneous:
with current regimens, the response rate is about
6070%, equally distributed between CR and PR,
but most patients cannot be considered cured. 37 In
fact, many of them require long-term maintenance
IST by CyA to sustain their response: even in recent
studies, CyA-dependency ranged between 25% and
50% of patients. 38-40 Nevertheless, relapses after an
initial response to IST are frequent: in about 3050%
of cases the disease reappears within months or
years from IST discontinuation. 38-40 In the most recent
experiences, the extension of CyA therapy beyond 6
months resulted in a reduction of the relapse rate; the
general recommendation is to taper CyA by 10% every
month, starting at least 1 year from IST. 41 Late relapses
remain possible, maybe also due to a suboptimal
therapeutic range of CyA in long-term responders
(due to tolerability or scarce compliance). Treatment
failure-free survival at 5 years may be estimated in the
range of 3050%, although overall survival remains
significantly higher (5585%), 38-40 because of available
salvage treatments (either further IST courses or
HSCT). In relapsed patients, the expected response rate
supplement to Journal of the association of physicians of india Published on 1st of every month 1st march, 2015 19
Table 1 : Indian data on IST
Study Patient no. OR OS f/u
George et al48 322 (Adults and children) 63% 67% 32 mths
Nair et al49 120 adults 85% 83% 76mths
Nair et al50 40 children 87% 85% 5 years
George et al51 70 children 43% 37% 38mths
Sharma et al52 35 children 50% - 40mths
OR-Overall Response; OS-Overall Survival; f/u-Follow up
to a second IST is 5070%, proving the principle that
standard IST may be insufficient in some patients 42-44.
In case of further relapses, even a third course of ATG
may be considered, although this strategy is usually
useless in refractory patients 45. However, given the
increased risk of systemic reactions, all these patients
are seeming candidates for alternative experimental
IST. Beside refractoriness and relapses, it has to be
noted that clonal evolution accounts for about 1015%
of treatment-failures 38,46 and solid tumours account for
an additional 10%. 47
Indian Data
We have limited Indian data published on IST in
AA summarized in Table 1. One of the largest adult
studies conducted in 322 patients showed an overall
response of 63 % with an overall survival of 67% at a
median follow up of 32 months. 48 Data from another
centre on 120 patients reported an overall response rate
of 85% at 6 months with an overall survival of 83% at
76 months. 49 Paediatric data on 40 patients is available
from the same centre with an overall response rate of
87.9% and overall survival of 90% at 24 months and
85% at 5 years. 50 However, data from other centres
do not show such high response rates as in an Indian
study in 70 children, which described a response rate
of 43% and an overall survival of 37%. 51 Another study
on 35 children showed a response rate of 50% to first
course of ATG, with the response going up to 57%
when a second course was included. 52
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