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2. medicine
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APLASTIC ANEMIA
Aplastic Anemia: First-line Treatment by Immunosuppression
and Sibling Marrow Transplantation
Jakob R. Passweg1 and Judith C.W. Marsh2
1Hematology
Division, Geneva University Hospital, Geneva, Switzerland; 2Department of Haematological
Medicine, King’s College Hospital, London, United Kingdom
Newly diagnosed aplastic anemia is a serious condition, with more than 75% (higher in young patients) becoming
long-term survivors if diagnosed and treated appropriately. First-line treatment approaches include immunosuppressive treatment using the combination of antithymocyte globulin and cyclosporine A for patients without a sibling donor
and HLA identical sibling transplant for patients younger than age 40 with a donor. Best transplant strategies have been
defined and include conditioning with cyclophosphamide and antithymocyte globulin, marrow as a stem cell source,
and graft-versus-host diease prophylaxis using cyclosporine A and methotrexate. It is against these standard
treatment approaches that any therapeutic progress has to be measured.
Aplastic anemia (AA) is defined as pancytopenia with a hypocellular marrow. The incidence of acquired AA in the Western hemisphere is around 2 per million population per year and higher in East
Asia. Age distribution shows peaks in children and young adults and
again in patients age ⬎ 60 years. AA is, in most cases, an acquired
autoimmune disorder; congenital AA is not the topic of this review.
Patients with AA commonly present with anemia and hemorrhage
and, more rarely, neutropenic infection. Severe AA (SAA) is
defined by at least two of the following: reticulocytes ⬍ 50 ⫻ 109/L
(or 20 ⫻ 109/L by manual counting), platelet count ⬍ 20 ⫻ 109/L,
and neutrophil count ⬍ 0.5 ⫻ 109/L. In very severe SAA (vSAA)
neutrophil counts are ⬍ 0.2 ⫻ 109/L. Often, the diagnosis is not very
clear at the outset. Marrow cellularity is not always easy to assess
and varies with age (ie, a normocellular marrow in an octagenerian
is considered hypocellular in a child). In healthy older patients,
subcortical marrow tends to be acellular. In general hypocellularity
by biopsy is more reliable than by cytology. Patients may require
more than one biopsy to confirm the diagnosis. Treatment decisions
are complex; a watch and wait strategy is often used initially in a
case of unexplained pancytopenia, but an interval from diagnosis to
treatment of more than 1 to 2 months may be associated with worse
outcome.1 Prior to treatment, the patient should be stable in terms of
controlling bleeding and treating infection. Spontaneous recovery is
rare. Once the patient is clinically stable, the disease is confirmed,
disease severity is assessed, and family typing done. It is usually
time to initiate treatment rapidly.
long-term cure (Figure 2). Unresolved issues are graft failure rates
of 4% to 14% and graft-versus-host (GVHD), severe acute GVHD
(grade III/IV)—which appears to occur less commonly now—and
chronic GVHD that still occurs in 30% to 40% of patients.
Allogeneic BMT from an HLA-identical sibling donor is recommended as first-line treatment if the disease is severe or very severe,
and if the patient is younger than age 40 years. There is controversy
concerning the upper age limit for BMT as a first-line treatment
because results vary in different case series. As shown in Figure 3, it
has been the current practice in Europe to analyze outcome after
BMT by age and to define an age cutoff with worse survival for
older patients. It appears that this cutoff is undergoing a shift toward
patients older than 50 years, as in more recent cohorts outcome of
patients in the ranges of 20 to 30 years, 30 to 40 years, and 40 to 50
years tend to be similar. The advantage of treating a patient with IST
and transplanting only in case of IST failure is appealing, but
outcome in patients undergoing transplantation after failing IST is
worse than undergoing transplantation upfront.3 In this study, the
hazard ratio for mortality was 1.7, compared with patients with
upfront transplantation. The recommendation within the recently
completed European Group for Blood and Marrow Transplantation
(EBMT) treatment algorithm is to use a cutoff of 40 years.
For patients with an HLA-identical sibling donor in whom transplantation is not used as first-line treatment, BMT remains an option as
second-line treatment in the case of IST failure.
First-line Treatment
Decision for first-line treatment will depend on patient age, availability of an HLA identical sibling donor, and, in part, on the severity of
the disease.2 Family typing is, therefore, recommended at first
suspicion of the disease. The standard first-line treatment for a
newly diagnosed patient with AA is either allogeneic bone marrow
transplantation (BMT) from an HLA-identical sibling donor or
immunosuppressive therapy (IST) with a combination of antithymocyte globulin (ATG) and cyclosporine A (CSA; ATG ⫹ CSA)
(Figure 1).
HLA-Identical Sibling Donor Transplantation
Transplantation for AA from an HLA-identical sibling donor has
improved considerably over the years, with a 75% to 80% chance of
36
Optimal transplantation strategies for HLA-identical sibling BMT
have been defined.
Stem Cell Source and Donor Selection
It is recommended bone marrow stem cells be used rather than
granulocyte-colony stimulating factor (G-CSF) mobilized peripheral blood stem cells (PBSCs). In a retrospective combined Center
for International Blood and Marrow Transplant Research (CIBMTR) and EBMT study, earlier engraftment occurred with PBSC
without difference in graft rejection. Survival was worse with more
chronic GVHD, using PBSC compared with bone marrow.4 Umbilical cord blood as an alternative source of stem cells for transplantation has been used in a small number of patients with AA. Outcome
American Society of Hematology
Figure 1. Treatment algorithm.
is excellent in the case of identical sibling cord (a situation that is
rare; ie, child with the disease of a mother who is pregnant), but
much less so with unrelated cord blood units. The effect of
sex-mismatch between donor and recipient has been evaluated in a
large retrospective EBMT. Survival was better in patients with
donors from the same sex. Male patients with female donors had
risks of acute GVHD increased by 33%, compared with male into
male transplant patients; female patients with male donors had
increased risks (220%) of graft rejection.5
Conditioning and GVHD Prophylaxis
Figure 2. HLA-identical sibling transplantation for AA as first-line
strategy, data reported to the EBMT database 1975 to 2009. Ten-year
survival is 34% ⫾ 8% for patients transplanted 1975 to 1980 (n ⫽ 142);
60% ⫾ 4% for patients transplanted 1980 to 1990 (n ⫽ 701), 73% ⫾
3% for patients transplanted 1990 to 2000 (n ⫽ 1377); and 79% ⫾ 2%
for patients transplanted 2000 to 2009 (n ⫽ 1951).
Figure 3. Impact of age on outcome after transplantation from an
HLA-identical sibling 1999 to 2009. In 2316 patients reported to the
EBMT database, irrespective of whether the transplant was the first or a
subsequent treatment. Five-year survival probabilities are 85% ⫾ 2%,
77% ⫾ 4%, 71% ⫾ 7%, 68% ⫾ 8%, and 48% ⫾ 10% in the age
groups ⬍ 20, 21 to 30, 31 to 40, 41 to 50, and ⬎ 50 years.
Hematology 2010
The conditioning regimens and GVHD prophylaxis described below
refer specifically to patients with acquired AA. In younger patients
with AA, the standard conditioning proposed by the Working Party
on SAA (WPSAA) is cyclophosphamide 50 mg/kg 32 ⫻ 4 ⫹ ATG.
This regimen is nonmyeloablative and highly immunosuppressive
to prevent graft rejection and GVHD. The benefit of adding ATG to
cyclophosphamide is unclear, because a recently published prospective randomized clinical trial (RCT) from CIBMTR showed no
37
significant benefit in terms of graft rejection, GVHD, and survival
rates, compared with cyclophosphamide alone.6 Raw unadjusted
data, from the EBMT database, show a slightly superior 10-year
survival of 85% versus 75% when ATG is used as part of the
conditioning regimen in sibling donor transplantation. The recommended posttransplant immunosuppression is CSA continued for at
least 12 months, with slow tapering and short course methotrexate—
the superiority of the combination having been confirmed in an
RCT,7 but the optimal duration of immunosuppression with CSA
posttransplant is not known. Because of unsatisfactory results with
older patients (eg, age ⬎ 30 or ⬎ 40 years) with sibling donor
transplantation, factoring in that most of these patients received a
transplant not as first-line, but as second-line treatment having a
longer interval from diagnosis to transplantation and a higher
transfusional load; several groups have tried to modify conditioning
by adding (eg, fludarabine) and by reducing the cyclophosphamide
dose. Some interesting series have been published,8 although no
prospective clinical trial has been run.
There is a significant risk of late graft failure in AA following
allogeneic BMT possibly associated with discontinuing CSA early.
Late graft failure may follow progressive mixed chimerism, defined
by ⬎ 10% recipient cells or ⬎ 15% increase over 3 months; rarely is
late graft failure hidden by autologous reconstitution.9,10 Stable
mixed chimerism is associated with excellent survival and a low risk
of chronic GVHD.
The EBMT WPSAA has recently activated an observational audit
(http://www.ebmt.org), where treatment recommendations for first
and subsequent lines of treatment are detailed for all age groups
incorporating the lessons learned in the trials as detailed previously.
The EBMT activity survey shows that bone marrow transplant
activity for marrow failure continues to increase in Europe, from
approximately 200 transplants per year in the early 1990s to about
600 transplants per year in 2008. This increase is, to a large part, due
to patients receiving transplants from unrelated donors, mostly after
having failed immunosuppression.11
Immunosuppressive Treatment
ATG and CSA
IST, using the combination of ATG ⫹ CSA, is associated with
response rates of 60% to 80%, with current 5-year survival rates of
around 75%.12–16 Survival is better in younger than in older patients,
as shown in Figure 4. Response definition includes a confirmation
by two or more blood counts at least 4 weeks apart, in patients not
receiving growth factors. Partial response is defined by transfusion
independence, whereas normalization of blood counts is required
for complete remission.17 Following ATG ⫹ CSA, patients should
be followed for response, relapse, and late clonal disorders, such as
paroxysmal nocturnal hemoglobinuria (PNH), myelodysplastic syndrome (MDS), and acute myeloid leukemia. There are no good
predictors of response to IST, although a recent study by the
National Institutes of Health (NIH) has shown that response at 6
months is associated with age, absolute reticulocyte count, and
absolute lymphocyte count.18 In a recent EBMT study randomizing
patients between concomitant treatment with G-CSF versus none,
neutrophil response to G-CSF was associated with better survival in
a post-hoc analysis.19 These factors are interpreted as reflecting
disease severity moreso than the true autoimmune nature of the
disease. Patients failing a first course of IST or relapsing after initial
response may respond to a second course.20,21 A second course
38
Figure 4. Survival at 10 years after immunosuppression as first-line
treatment strategy in 3202 patients treated between 1975 and 2009 by
decade (1970s, 1980s, 1990, and 2000s), and reported to the EBMT
database.
should not be initiated earlier than 4 to 6 months after the first
course, because it usually takes more than 3 months before a
response occurs. There is a 30% to 60% chance of response to a
second course. There are patients refractory to two courses of IST
who will not respond to a 3rd and who are considered true IST
refractory cases.22 In these patients, the pathophysiology of the
disease may be different, although there are no tools at this point in
time to distinguish them from responding AA patients. Early
identification of IST refractory cases is obviously needed, because
these patients may be treated by other means (eg, alternative donor
stem cell transplantation).
To analyze long-term outcome event-free survival is much more
important than survival alone; events are defined as primary
nonresponse, relapse, and secondary clonal complications, such as
MDS/leukemia and PNH. Event-free survival after ATG ⫹ CSA is
typically in the 35% to 50% range at 5 years.12 Response to ATG
and CSA occurs late, typically 3 to 6 months after treatment.
Response is stable in many patients, but relapse may occur. This is
typically reported to be around 30% within the EBMT; reported
rates vary among groups. Patients are at risk of late clonal
complications; typically, rates are around 8% for MDS/acute
myeloid leukemia, 10% for hemolytic PNH, and 11% for solid
tumors at 11 years, as reported by the German SAA Study Group.
First-line treatment by IST is indicated for patients not eligible for
sibling donor BMT. This includes patients with transfusiondependent, nonsevere AA and patients with SAA or vSAA who are
age ⬎ 40 years and younger patients with SAA or vSAA who lack
an HLA-compatible sibling donor. For patients who are not
transfusion- dependent, it may be reasonable to follow the patient
without intervention.
ATG is a powerful immunosuppressive, and its use in severely
neutropenic patients requires careful monitoring, prophylaxis, and
American Society of Hematology
Table 1. Different brands of antithymocyte globulin
T-ALL indicates T-cell acute lymphoblastic leukemia.
treatment of infections, as well as adequate (and sometimes
intensive) platelet transfusional support. In Europe, the standard
preparation of ATG has until recently been horse ATG (Lymphoglobuline; Genzyme Corporation, Cambridge, MA) whereas in the
United States, ATGAM Company (Upjohn, Kalamazoo, MI) has
been used in a slightly different dosage. All large European
Cooperative Studies have been done using horse ATG. The
European preparation has been recently withdrawn from the market
and replaced by a rabbit ATG (Thymoglobuline; Genzyme), up to
now used for second or subsequent courses of IST 21,23 (Table 1).
Response rates to rabbit ATG are anticipated to be similar to horse
ATG, based on response rates to second courses of IST, the same
immunogen (thymocytes), a similar production method binding to
similar epitopes. Thymoglobulin is more immunosuppressive than
the previously used horse ATG. It results in a more prolonged
period of lymphopenia, has a longer half-life, and has a higher
affinity to human lymphocytes. To date, there have been only
limited studies using rabbit ATG as first-line treatment for AA. In a
small single center phase II study of 13 patients with AA and 12
patients with low-risk MDS, among the patients with AA, there
were five complete responses and seven partial responses.24 A study
from Brazil observed lower response rates when comparing patients
treated by rabbit ATG with historical controls treated with horse
ATG,25 whereas a Spanish group showed similar results in 79
patients.26 A comparative NIH study of horse (ATGAM) versus
rabbit ATG (Thymoglobuline) is awaiting completion. A large
prospective randomized study from China, with four arms, showed
no benefit from growth factors added to horse ATG ⫹ CSA,
confirmed that the combination of horse ATG ⫹ CSA was superior
to horse ATG alone and superior to a different rabbit ATG
preparation in combination with CSA. This ATG is only available in
Europe and is generated by stimulating the animals with T-cell acute
lymphoblastic leukemia blasts from the Jurkat cell line instead of
thymocytes.14
ATG is given for 5 days as a daily intravenous infusion over 12 to
18 hours through a central venous catheter. There is a pronounced
first-dose effect, with fever and rigors that will respond to steroids
and reduction of infusion speed. Corticosteroids (1 mg/kg) and
acetaminophen are given prior to each daily dose of ATG. Steroids
are to prevent serum sickness and are tapered slowly over 4 weeks.
Steroids do not contribute to response in AA patients, and prolonged
Hematology 2010
treatment is to be avoided. Serum sickness typically occurs between
days 7 and 14 from the start of ATG treatment. Symptoms include
myoarthralgia, rash, fever, proteinuria, and platelet consumption.
Oral CSA at 5 mg/kg/day may be started with ATG. We usually aim
for CSA blood level between 150 and 250 ␮g/L, although there are
no data on optimal levels in this disease. An Italian study showed
reduced risks of relapse with prolonged CSA treatment; this has to
be balanced against the side-effect profile of long-term CSA
administration.27
The decision whether to use ATG in older patients can be difficult
and requires careful assessment and discussion of the risks with the
patient. For older patients, the response rate and survival rate are
lower, compared with younger patients. The response rate for
patients aged ⬎ 60, 50 to 59, and ⬍ 50 years is 37%, 49%, and 57%;
5-year survival is 50%, 57%, and 72%, respectively. For patients
aged ⬎ 70 years, the 10-year survival is 33%, compared with 60%
for those aged between 50 and 70 years.28,29 Although there is no
upper age limit for ATG treatment, consideration for treatment
should be preceded by medical assessment to exclude significant
comorbidities. CSA treatment alone may be considered. The current
EBMT treatment algorithm proposes to treat hospitalized patients
who are severely ill by ATG ⫹ CSA, if considered to be tolerable
considering the comorbidity profile, whereas to start newly diagnosed patients who are well and in an outpatient setting with CSA
alone.
Other Immunosuppressants
High-dose cyclophosphamide without stem cell support is used by
the Johns Hopkins Group as treatment for patients with newly
diagnosed AA with roughly comparable response rates in newly
diagnosed patients, compared with ATG ⫹ CSA.30 A prospective
randomized study comparing this against ATG and CSA was
terminated early because of excess deaths and fungal infections in
the cyclophosphamide arm.31 Therefore, high-dose cyclophosphamide without stem cell support could not be recommended as
first-line, in light of the data given. Its place, if any, in second-line or
third-line treatment is not defined and has to be compared with
alternative donor transplant strategies, other immunosuppressive
strategies, and treatment by supportive care alone.
Mycophenolate mofetil inhibits the proliferation of B and T
lymphocytes, and has been used in organ transplantation and
autoimmune disorders. The EBMT WPSAA has recently performed
a pilot study of 17 refractory patients without response.32 A study
from the NIH showed no improvement in response or reduction in
relapse after ATG ⫹ CSA when mycophenolate mofetil was
added.33
Alemtuzumab (Campath-1H) is currently being investigated for
refractory AA in prospective trials at the NIH and retrospectively by
the EBMT, with a response rate of about 60% in a limited cohort of
35 heterogeneous patients.34
It is the group at the NIH who has the merit of initiating new studies
trying to improve results of immunosuppressive treatment beyond
what has been achieved by ATG ⫹ CSA more than 20 years ago.
Recent improvement in outcome is probably more due to improved
supportive care than to novel concepts of immunosuppressive
treatment. A recent study adding sirolimus to ATG ⫹ CSA has not
shown improved results35; on the other hand, there have been
interesting response rates reported with daclizumab, an antibody
39
directed against the interleukin-2 receptor,36 in patients with disease
of moderate severity.
Supportive Care
Transfusional Support
Red cell and platelet transfusions are essential for patients with AA
to maintain safe blood counts. Platelet transfusions should be given
prophylactically when platelet count is ⬍ 10 ⫻ 䡠109/L or ⬍ 20 ⫻
䡠109/L in the presence of fever. A common problem in multitransfused patients with AA is that they may develop alloimmunization
to leukocytes present in red cell and platelet transfusions by
generating anti HLA- (or non-HLA) antibodies. This can result in
platelet refractoriness, as well as an increased risk of graft rejection
after allogeneic BMT. Apart from transfusional support, practical
measures to help prevent bleeding include dental hygiene, oral
tranexamic acid, and control of menorrhagia with progestagens.
Although there are no data on transfusion-induced GVHD in
recipients of IST, experts recommend to universally use irradiated
blood products during and after ATG therapy.37 There is, however,
no consensus for how long after treatment to maintain this
recommendation.
Infection Prevention and Treatment
Infectious complications in patients with SAA have been reviewed
recently.38 The risk of infection is determined by the neutrophil
counts. There is a wide variability in susceptibility to infectious
complications. There is also an important difference between
patients with a very low, but stable, neutrophil count (eg, 0.1– 0.2 ⫻
109/L) that may be sufficient to protect from most infections and
patients with no neutrophils at all in their blood smear. Patients with
AA are at risk of bacterial and fungal infections. Aspergillus
infections have a very high mortality in patients with SAA and
vSAA because of prolonged and severe neutropenia. AA patients
who are severely neutropenic should ideally be cared for in isolation
when in the hospital and should receive prophylactic antibiotics,
antifungals, and regular mouth care (including antiseptic
mouthwash).
As for all neutropenic patients, fever will require immediate
hospitalization and treatment before the results of bacterial investigations are available. The local hospital guidelines for treatment of
febrile neutropenia should be followed. This may include a combination of aminoglycosides and a ␤-lactam antibiotic, the exact
choice depending on local hospital microbiologic sensitivity/
resistance patterns. The duration of neutropenia, the patient’s
infection history, and recent antibiotics will also influence the
choice of antibiotic, including the early introduction of broadspectrum antifungals. Early use of an appropriate lipid formulation
of amphotericin or one of the newer antifungal agents, such as
Voriconazole or Caspofungin, should be considered in AA patients
who may need prolonged treatment. Pulmonary infiltrates and sinus
infection should be taken as indicators of likely fungal infection in
patients with SAA. There have been no controlled studies evaluating the use of G-CSF or other hemopoietic growth factors in the
treatment of severe infection in patients with AA. A short course of
subcutaneous G-CSF at a dose of 5 ␮g/kg/day may be considered in
neutropenic infection, if the patient has not been proven to be
refractory to growth factors. G-CSF may produce a temporary
neutrophil response, but usually only in those patients with residual
marrow granulocytic activity. If there is no response by 1 week, it is
reasonable to discontinue the drug.
40
Growth Factors
The rationale for using G-CSF after ATG ⫹ CSA is to attempt to
reduce the risk of infection during the 3 months before neutrophil
response is expected and to possibly improve response. However,
prolonged use of growth factors may increase the risk of late clonal
disorders, as shown by a retrospective EBMT WPSAA study.39 No
study has ever shown an increase in trilineage response by the use of
G-CSF. In a prospective Japanese study, the risk of relapse after
response was decreased in the G-CSF arm. In a recent EBMT study,
the association of ATG ⫹ CSA with G-CSF was associated with
higher neutrophil counts, and less infection and hospitalization for
the duration of G-CSF administration.19 Given these conflicting
data, the EBMT WPSAA currently recommends to limit the use of
G-CSF after ATG ⫹ CSA to patients with neutropenic infection.
Androgens
Androgens were used extensively in the treatment of AA for many
decades before the availability of immunosupressants. In some
patients, oxymetholone can stimulate erythropoiesis and rarely can
produce a trilineage response; recent work has shown that androgens increase telomerase by indirect upregulation of the TERT
(telomere reverse transcriptase) promoter.40 In combination with
ATG, they increase response, but are hepatotoxic. Because of
virilization, they are often unacceptable to women. The value of
androgens in this disease, especially in refractory patients who are
not candidates for alternative donor transplantation, needs to be
reassessed in the current era.
Iron Chelation
Iron overload can cause problems in heavily transfused patients.
Subcutaneous desferrioxamine should be started when serum ferritin is ⬎ 1000 ␮g/L, although evidence for this recommendation is
lacking. This also needs to be assessed on an individual basis, in
view of the risk of local hemorrhage and infection from subcutaneous injections. Alternatives are the oral iron chelator deferiprone,
but this drug is associated with a risk of agranulocytosis. The novel
oral iron chelator deferasirox is available for use in transfusiondependent anemia. There is not sufficient data to assess the
cytopenia risks associated with deferasirox treatment in AA patients, case-by-case decisions have to be made. For patients with
iron overload with response to ATG ⫹ CSA or to BMT, venesection
is the standard way to remove iron.
Patients with AA should be followed indefinitely to monitor for
relapse and later for clonal disorders, such as MDS, leukemia, PNH,
and solid tumors.
Disclosures
Conflict-of-interest disclosure: The authors declare no competing
financial interests.
Off-label drug use: None disclosed.
Correspondence
Jakob R. Passweg, MD, MS, Hematology Division, Geneva University Hospital, Rue G Perret-Gentil 4, 1211 Geneva 14, Switzerland;
Phone: ⫹41 22 3723958; Fax: ⫹41 22 3727288; e-mail:
[email protected]
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