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Published in final edited form as:

Expert Rev Hematol. 2011 April ; 4(2): 221230. doi:10.1586/ehm.11.11.

Clinical management of aplastic anemia

Amy E DeZern1 and Robert A Brodsky,2
1Division of Medical Oncology, Department of Medicine, The Johns Hopkins School of Medicine,
720 Rutland Avenue Ross Research Building, Room 1025, Baltimore, MD 21205, USA
2Division

of Hematology, Department of Medicine, The Johns Hopkins School of Medicine,

Baltimore, MD, USA

Abstract

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Acquired aplastic anemia is a potentially fatal bone marrow failure disorder that is characterized
by pancytopenia and a hypocellular bone marrow. Hematopoietic stem-cell transplantation or bone
marrow transplantation (BMT) is the treatment of choice for young patients who have a matched
sibling donor. Immunosuppression with either anti-thymocyte globulin and cyclosporine or highdose cyclophosphamide is an effective therapy for patients who are not suitable BMT candidates
owing to age or lack of a suitable donor. Results of BMT from unrelated and mismatched donors
are improving, but presently this treatment option is best reserved for those patients who do not
respond, relapse or develop secondary clonal disorders following immunosuppressive therapy.
Efforts are currently underway to both improve immunosuppressive regimens and to expand the
application of BMT.

Keywords
anti-thymocyte globulin; aplastic anemia; bone marrow failure; bone marrow transplantation;
cyclosporine; hematopoietic stem-cell transplantation; high-dose cyclophosphamide; paroxysmal
nocturnal hemoglobinuria

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Aplastic anemia (AA) was first described in a pregnant woman in 1888 [1]. The term now
refers to a clinical syndrome defined as pancytopenia with a hypocellular bone marrow in
the absence of abnormal infiltration or increased reticulin. AA can be inherited or acquired.
The inherited marrow failure syndromes include disorders such as Fanconi anemia,
dyskeratosis congenita and SchwachmanDiamond syndrome. Our understanding of the
molecular basis for these disorders has progressed in recent years and the genetic defects
have been mapped to DNA damage repair mechanisms (Fanconi anemia) [2], telomerase
dysfunction (dyskeratosis congenita) and ribosomal function (SchwachmanDiamond
syndrome) [3,4]. Acquired AA is usually the result of an autoimmune attack that appears to
be directed at hematopoietic stem/progenitor cells [57]. The objective of this article is to
summarize the current literature on treatment strategies in acquired AA and to discuss
promising approaches in the management of patients with severe AA.

2011 Expert Reviews Ltd

Author for correspondence: Tel.: +1 410 502 2546 Fax: +1 410 955 0185 [email protected] .
Financial & competing interests disclosure The authors have no other relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript
apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.

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Diagnosis of acquired aplastic anemia

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Acquired AA can occasionally be traced to a distinct trigger such as seronegative hepatitis,

drugs, toxins or pregnancy, but the vast majority of cases are classified as idiopathic.
Clinical manifestations are proportional to the peripheral blood cytopenias and may include
dyspnea on exertion, fatigue, easy bruising, petechiae, epistaxis, gingival bleeding, heavy
menses, headache and fever. A complete blood count, leukocyte differential, reticulocyte
count and a bone marrow aspirate and biopsy can establish the diagnosis. Peripheral blood
flow cytometry to detect cells missing glyco sylphosphatidylinositol anchored proteins
(GPI-AP) [810], bone marrow karyotyping and FISH to help exclude hypoplastic myelo
dysplastic syndromes (hMDS) should be performed on all patients. GPI-AP deficiency is a
hallmark of paroxysmal nocturnal hemoglobinuria (PNH); however, small-to-moderate
populations of GPI-AP deficient cells (usually 0.115%) can be found in most patients with
acquired AA at diagnosis [11]. Finding a PNH clone in patients with AA can be helpful in
excluding congenital forms of the disease.

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A hypocellular bone marrow biopsy is required for the diagnosis of AA. Spicules from an
aspirate may be surprisingly cellular in some patients despite overall marrow hypo
cellularity as most patients will have residual pockets of ongoing hematopoiesis. Thus, a 12
cm core biopsy is essential for assessing cellularity. Mild dyserythropoiesis is not
uncommon in AA, especially in cases with simultaneous small-to-moderate sized PNH
populations; however, the presence of a small percentage of myeloid blasts or dysplastic
features in the myeloid or megakaryocyte lineages favors a diagnosis of hMDS [12,13].
Distinguishing between AA and hMDS is often challenging, especially in older patients. The
percentage of CD34+ cells in the bone marrow is often helpful [12]. The percentage of
CD34+ cells is usually <0.3% in AA, whereas the CD34+ percentage is either normal (0.5
1.0%) or elevated in hMDS. Blood from the initial aspirate should be tested for
chromosomal abnormalities via cytogenetics and FISH. Abnormal cytogenetic studies at the
time of diagnosis may suggest an alternative diagnosis, it may be an independent predictor
of poor response to immunosuppressive therapy and may be associated with a higher
cumulative leukemic transformation rate [14].

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Aplastic anemia is classified as non-severe (NSAA), severe (SAA) and very severe based on
the degree of the peripheral blood cytopenias (Box 1). The 2-year mortality rate with
supportive care alone for patients with SAA or very severe AA approaches 80% [6], with
invasive fungal infections and overwhelming bacterial sepsis being the most frequent causes
of death. The clinical course of NSAA is quite variable, it is seldom life-threatening and in
many instances requires no therapy [15]. In a recent review of 96 NSAA patients in Korea
from 19972007, 41.7% of the patients were initially asymptomatic. A total of 62 patients
were treated with oxymetholone, anti-thymocyte globulin and cyclosporine, cyclosporine
alone or other agents after initial diagnosis. During the follow-up period, 18 patients
progressed to SAA and the median progression time was 18 months. Initial white blood cell
count and absolute neutrophil count in the evolution group tended to be lower than in the
group that did not progress. A total of 16 patients showed overall improvement, whereas
three patients developed secondary hematologic disease, acute myeloid leukemia (AML),
myelodysplastic syndrome (MDS) and PNH. Their data suggest that low pretreatment levels
of white blood cells and absolute neutrophils are associated with progression to more severe
disease. Furthermore, patients with thrombocytopenia that did not respond to treatment with
immunosuppression had a higher frequency of progression (33%) to SAA [16].

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Initial supportive care

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Before initiating more definitive therapies for acquired SAA, the clinician must consider the
significant supportive care required for these patients. An individual patients requirement
for supportive care will depend upon the severity of symptoms and pancytopenia.
Transfusions

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Patients with severe cytopenias require urgent support with blood products. Blood products
should be irradiated to prevent transfusion associated graft-versus-host disease (GVHD)
[17,18], and filtered to reduce the incidence of viral infections and prevent alloimmunization
[19]. Transfusions from family members should be avoided to decrease sensitization to
potential bone marrow donors. The initial goal of transfusion therapy for anemia should be
to correct or avoid cardiopulmonary complications. Most patients without significant
comorbidities should be transfused with packed red blood cells when symptomatic. The goal
of platelet transfusion should be to maintain a high enough platelet count to prevent
spontaneous bleeding. For most patients, platelet transfusions are indicated when platelet
levels are below 10,000/ul or if the patient is experiencing bleeding. Granulocyte
transfusions remain controversial in AA and should be used judiciously. A recent study of
granulocyte infusions in patients with SAA showed a potential role in patients with severe
bacterial or fungal infections. A retrospective analysis was performed on all patients with
SAA who had received granulocyte transfusions between 1997 and 2007 in a single
institution. Infections in the study patients were both invasive bacterial and fungal infections
unresponsive to maximal antibiotic and/or anti fungal therapy. The overall survival (OS) to
hospital discharge was 58%. Survival was strongly correlated with hematopoietic recovery.
The mean post-transfusion absolute neutrophil count did not differ significantly in either the
responders or nonresponders. The data suggest that granulocyte transfusions may have an
adjunctive role in severe infections in patients with SAA [20].
Growth factors

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The use of HGFs to support blood counts is of limited value in SAA, as predicted by both in
vitro studies and measurement of endogenous serum levels of HGF, which are markedly
elevated. There may be a limited role for granulocyte colony stimulating factor (G-CSF)
administration in an attempt to stimulate a neutrophil response in the presence of severe
infection, although there have been no prospective randomized studies showing a benefit for
G-CSF in SAA patients [21]. In France, a randomized multicenter study was conducted to
evaluate the efficacy and safety of G-CSF during the first 12 weeks of standard
immunosuppressive therapy (IST) in 102 patients with untreated SAA. At a median
followup of 5 years, no difference was observed between the group who received G-CSF
and those who did not in terms of survival, hematological response and occurrence of
secondary leukemias (one patient in each group). These data suggest that G-CSF support
with IST might be used for patients with SAA as it significantly enhances neutrophil
recovery but it must be recognized that it does not modify the overall response and survival
[22]. Another randomized multicenter study of over 100 previously untreated patients with
SAA in Japan also demonstrated no survival benefit of G-CSF with IST. Two secondary
leukemias were also reported in this trial [23]. A systematic review and meta-analysis of
data from the Annual Meeting of the American Society of Hematology (20022007), the
European Group for Blood & Marrow Transplantation (EBMT; 20022008), the Annual
Meeting of the European Hematology Association (20022007) and the Annual Meeting of
the Society for Hematology and Stem Cells (20022007) demonstrated that treatment with
growth factors (erythropoietin or G-CSF) does not affect mortality rate or improve complete
and overall hematologic response. Likewise, growth factors do not alter the occurrence of
refractory disease, the rate of clinically documented or severe infections, but are associated

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with a decreased risk of relapse [24]. There are also data suggesting that HGFs may have a
deleterious effect in SAA. In a retrospective survey among 840 patients with SAA registered
by the EBMT who received immunosuppressive therapy with or without G-CSF, a small but
significant increase in hazard (1.9) of AML/MDS was reported in the G-CSF-treated group
[25,26].
Infections

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Fungal and bacterial infections are a major cause of death in patients with SAA. Data from
children suggest that mortality from fungal infections is higher in patients with SAA than in
patients with AML or acute lymphoblastic leukemia [27]. However, an active fungal
infection should not delay more definitive therapy such as IST or bone marrow transplant
(BMT) [28]. In contrast to the high incidence of aspergillus infections, Pneumocystis
jiroveci infections are rare among patients with SAA, given that T cells are not defective
[29]. Patients with SAA are at risk for all types of infections including Gram-positive as
well as Gram-negative infections [30]. There is no standardized approach to antibiotic
therapy in these patients. A recent case report suggests that continuous-infusion -lactam
antibiotics are a potentially useful treatment strategy for resistant Pseudomonas aeruginosa
infections in immunocompromised patients [31]. Patients are also susceptible to viral
infections, particularly community-acquired respiratory viruses, members of the
Herpesviridae family and the viral hepatitides. Vigilance and proactive prescription of
prophylactic antibiotics (when deemed clinically appropriate), antivirals and antifungals in
this patient population is imperative [29].
Definitive treatment

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Hematopoietic stem-cell transplantationBone marrow transplantation is potentially

curative and is the treatment of choice for children and young adults (age of <30 years) with
SAA who have an HLA-matched sibling donor. An advantage of BMT over standard IST is
a marked reduction both in the risk of relapse and the evolution of late clonal disorders such
as MDS and PNH [32]. A recent report from the EBMT of over 1500 patients confirmed that
predictors of survival following BMT included matched sibling donor, age of less than 16
years, early transplant (time from diagnosis to transplant of less than 83 days) and a nonradiation conditioning regimen [33]. Most patients achieve full donor chimerism after BMT;
however, early and late graft rejection with persistent pancytopenia may occur. Patients with
a progressive increase in host cells >5%, especially around the time of withdrawal of
immuno suppressive therapy, appear to have the greatest risk of late graft failure. Graft
rejection is a greater obstacle for unrelated transplants. The rate of late graft failure is lower
in patients who achieve full donor chimerism by 1 year or those patients with stable mixed
chimerism (<5% host) at 1 year. This observation suggests a benefit of serial assessment of
donor chimerism prior to withdrawing IST [34]. Interestingly, graft failure is not always
deleterious in acquired SAA since autologous recovery may occur following
cyclophosphamide (CY)-based condition therapy [35,36]. A recent retrospective ana lysis of
1024 consecutive patients in the AA Working Party of the EBMT showed a cumulative
incidence of autologous recovery at 4.2% (95% CI: 3.15.6%). OS at 10 years was 84% for
patients demonstrating host recovery, 74% for engrafted patients, and just 16% for nonengrafted patients who did not experience autologous reconstitution of hemato poiesis [37].
The EBMT reviewed outcomes in nearly 700 patients with SAA receiving transplants from
HLA-matched siblings. A total of 134 grafts were peripheral blood progenitor cell grafts,
and 558 were bone marrow grafts. In patients older than 20 years of age, chronic GVHD and
overall mortality rates were similar after both types of transplantations. In patients younger
than 20 years of age, rates of chronic GVHD (relative risk 2.82; p = 0.002) and overall
mortality (relative risk 2.04; p = 0.024) were higher after transplantation of peripheral blood
progenitor cell grafts than after transplantation of bone marrow. In younger patients, the 5Expert Rev Hematol. Author manuscript; available in PMC 2012 February 1.

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year OS was 85% after BMTs but only 73% after peripheral blood progenitor cell grafts.
These data suggest that bone marrow grafts are preferable in young patients undergoing
HLA-matched sibling donor transplantation for SAA [38].

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ConditioningCyclophosphamide (50 mg/kg/day 4 days) with or without antithymocyte globulin (ATG), is commonly used for conditioning before BMT in patients with
SAA. Although this regimen is non-myeloablative, the immunosuppression is sufficient to
allow engraftment in most cases [3941]. Avoidance of total body irradiation (TBI) and
busulfan markedly reduces transplant-related complications such as mucositis, GVHD,
second malignancies and infertility. Survival rates following matched sibling allogeneic
BMT have steadily improved since the 1970s largely because of improved supportive care,
especially in the area of GVHD prophylaxis [40]. A recent randomized controlled study of
CY with and without ATG demonstrated that graft failure and GVHD were similar, and the
addition of ATG did not improve OS [42]. Fludarabine (FLU) has been added to CY
conditioning in SAA patients in an attempt to decrease graft failure and improve OS. In a
small cohort of young patients (median age 20 years), 38 patients were treated; 24 were
treatment naive, 11 had failed previous IST and three had failed hematopoietic stem-cell
transplantation previously. The FLU/CY regimen was well tolerated with minimal
transplant-related mortality. Engraftment was observed in all patients. The median time for
engraftment of neutrophils and platelets was 18 and 23 days, respectively. Graft rejection
with a relapse of aplasia was observed in one patient. The OS at 43 months post-transplant
was 79% [43]. Larger studies are necessary to determine what role FLU and CY will have as
our transplant experience continues. The use of FLU-based regimens has enabled
engraftment in heavily transfused and sometimes alloimmunized patients [44].

Choice of donor: HLA-matched siblings or alternative donors

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Fewer than 30% of patients will have an HLA-matched sibling donor. Unfortunately,
unrelated donors and mismatched transplants have almost twice the transplant-related
mortality and risk of GVHD as matched sibling donor transplants [45]. Thus, BMT from
unrelated or mismatched donors is usually reserved for patients who fail to respond to one or
more courses of IST. Among patients who do receive unrelated or mismatched transplants,
the best results are seen in patients under the age of 21 years with disease duration of less
than 1 year [4547]. The International Bone Marrow Transplant Registry reported on the
results of 318 alternative donor transplants in patients with SAA between 1988 and 1998
[48]. Most patients in this series were young, heavily transfused and of poor performance
status. The probability of graft failure was 20% and the survival probability at 5 years was
less than 40%. The Fred Hutchinson Cancer Research Center (Seattle, WA, USA) reported
on the results of unrelated allogeneic BMT in SAA after conditioning with low-dose TBI,
high-dose CY and ATG [49]. The median age was 19 years, and with a median follow-up of
7 years, 61% of HLA-identical and 40% of HLA nonidentical transplant recipients survived
the procedure; however, more than 70% of patients acquired acute GVHD and over 50%
developed chronic GVHD. A recent meta-ana lysis of 18 heterogeneous trials evaluated the
outcomes for patients who received unrelated donor transplants after failure to respond to
IST. This suggests that a stable performance status and detailed HLA-matching contribute to
improved survival [50]. A review of data from the EBMT was performed to determine
further outcomes for patients receiving BMT from an unrelated donor for SAA. They
analyzed 498 patients transplanted during 19902005. Survival at 5 years increased from
328% before 1998 to 578% after 1998 (p < 0.0001). After 1998, there was less graft
failure (11 vs 26%; p < 0.0001), less acute GVHD (cumulative incidence 28 vs 37%; p =
0.02) and less chronic GVHD (22 vs 38%; p = 0.004). The authors suggest that these
improvements in outcomes are due to better donor matching [51]. A more recent ana lysis
from the EBMT-SAA working party retrospectively reviewed the outcome of 100 patients
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undergoing an alternative donor transplant, after IST had failed. All patients received a
combination of FLU, CY and ATG with or without low dose (2 Gy) TBI as conditioning.
The actuarial 5-year survival was 73% for the group that received FLU, CY and ATG (FCA)
and 79% for the group given the conditioning regimen including TBI. The most significant
predictor of survival was the interval between diagnosis and transplantation, with 5-year
survival rates of 87 and 55% for patients grafted within 2 years of diagnosis and more than 2
years after diagnosis, respectively (p = 0.0004). The overall cumulative incidence of acute
GVHD grades IIIV and IIIIV was 18 and 7%, respectively, with no difference between
the two regimens. Chronic GVHD was recorded in 27% of the FCA group and 50% of the
FCA-TBI group (p = 0.06). This study confirms that outcomes are improving for SAA
patients undergoing alternative donor transplants [52].
GVHD prophylaxis

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A major cause of morbidity and mortality for patients undergoing BMT, especially in older
patients and in alternative donor transplants, is GVHD. The most commonly used GVHD
prophylaxis is a calcineurin inhibitor such as tacrolimus or cyclosporine A (CsA) [53]. The
combination of methotrexate (MTX) and CsA (MTX-CsA), as well as the combination of
mycophenolate mofetil (MMF) and CsA (MMF-CsA) have been successfully used for
GVHD prophylaxis. In a recent prospective trial of 47 patients, MMF-CsA (compared with
MTX-CsA for acute GVHD prophylaxis) showed equivalent rates of OS and event-free
survival at 2 years [54]. Research into GVHD prophylaxis for unrelated donor
transplantation is also ongoing. A retrospective comparative ana lysis using 47 matched
pairs, of tacrolimus/MTX and CsA/MTX showed improved 5-year OS in the tacrolimus
group (82.8%) compared with 49.5% in the CsA group (p = 0.0124) [55]. Interest has
recently turned towards high-dose CY as GVHD prophylaxis. Investigators from Johns
Hopkins (MD, USA) have demonstrated in mice that high-dose post-transplantation CY
facilitates partially HLA-mismatched hematopoietic stem-cell transplantation without severe
GVHD [56] and can mitigate, if not completely nullify, the negative impact of HLAdisparity on transplantation outcome. High-dose CY is also effective as single agent, shortcourse prophylaxis of GVHD after nonmyelo ablative conditioning and HLA-matched
allogeneic-BMT in humans [57]. Recently, this same group reported successful use of highdose post-transplantation CY as GVHD prophylaxis in two patients with refractory SAA;
both patients were over 50 years of age and neither developed GVHD [58].
Immunosuppressive therapy

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Compared with BMTAnother highly effective therapy for SAA is ATG and CsA IST
and is generally first-line therapy for SAA patients who lack matched sibling donors or are
not good candidates for BMT. The hematopoietic response rate after ATG/CsA is 6070%
and the probability of survival at 5 years ranges from 60 to 85% [59,60]. However, up to
40% of patients eventually relapse [60]. In a recent outcomes study from the EBMT of 2479
patients with SAA, actuarial survival analyses were performed according to whether the
patients first-line treatment was BMT or IST. At 10 years the survival was 73% in BMT
recipients and 68% in those treated with IST (p = 0.002). The rates of secondary malignancy
were tenfold higher in the patients who received IST alone (1.2%) compared with those who
received BMT (0.1%) [60,61].
IST for NSAAThere is only one prospective randomized trial of CsA alone or the
combination of ATG/CsA treatments in patients with NSAA. In this study the end point was
the hematologic response at 6 months. A significantly higher overall response rate of 74%
was found in the ATG and CsA group, with 57% complete and 17% partial responders (p =
0.02). Compared with CsA alone, the combination of ATG and CsA resulted in a
significantly higher median hemoglobin level and platelet count at 6 months. The survival
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probabilities for the two groups were comparable at 93% for the CsA group and 91% for the
ATG/CsA group [62].

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IST for SAAIn patients with SAA, there is a prospective randomized trial of the addition
of sirolimus to the combination of ATG/CsA in which this agent did not improve the
response rates for these patients [63].
Tacrolimus as an alternative to CsA has been investigated in children with SAA and found
to have comparable responses rates (88 vs 85%) with a more favorable side effect profile
[64].

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Additional immunosuppressive drugs such as MMF have been added to the ATG/CsA
combination with the aim of decreasing relapse and secondary clonal disease. However, as
yet no improvement in response of relapse rates has been observed when compared with the
standard ATG/CsA [65]. PNH may also arise following IST for SAA. A recent retrospective
ana lysis was performed for PNH clones measured by flow cytometry in over 200
consecutive SAA patients who received IST from 20002008. In the 60% of patients
without a detectable clone pretreatment, the appearance of a clone after IST occurred at least
once in 21% of the patients but persisted in only 10%. However, in 30 patients, an increase
in clone size was observed after IST. The majority of these patients did not require specific
interventions with anticoagulation and/or eculizumab over a follow-up period of just 24
months. Of the seven patients who did require therapy for clinical PNH symptoms and signs,
all had an elevated lactate dehydrogenase and a clone size greater than 50%. Of the patients
who did have a detectable clone at diagnosis, only ten patients lost this clone after IST. The
remaining 73 patients with a clone at diagnosis experienced a gradual decrease in the PNH
clone size, noted in the months following IST [66].

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IST in older patientsThe outcomes for tolerability and toxicity, response and relapse
rates were examined in 24 older patients (over 60 years of age) receiving IST. Seven
patients received standard IST consisting of standard-dose ATG with or without CsA, and
17 patients received attenuated IST consisting of at least a 50% dose reduction of ATG with
CsA or CsA alone. Six patients (25%) had early deaths, mostly due to infection. Early
mortality appeared higher in the standard IST group, although this was not statistically
significant (43 vs 18%; p = 0.4). The 2-year cumulative incidence of response was 42%
(95% CI: 2669%). Responders had significantly better survival than non responders (p =
0.0002). The 3-year probability of OS was 49% (95% CI: 2768%). Nine out of 14
evaluable patients in the attenuated IST group had durable responses to treatment. These
data from this small cohort suggest that attenuated dose IST could be a reasonable treatment
option for patients deemed unfit for standard-dose IST [67].
There are currently no standard criteria to deem IST a treatment failure. Many institutions
use 4 months of IST without response to deem that treatment was ineffective before moving
to a secondary treatment. Prognostication for response to IST is an ongoing area of research.
It is known that telomere mutations and shortening can be found in bone marrow failure
syndromes such as dyskeratosis congenita [68]. The determination of telomere length is
useful for the characterization of many bone marrow failure disorders, including SAA, by
the quantitative (q)PCR method [69]. Interest in determination of the clinical significance of
short telomeres in SAA prompted an ana lysis of 183 patients at the National Heart Lung
and Blood Institute (MD, USA). All patients had pretreatment measurements of telomere
length and were subsequently enrolled into immunosuppression protocols. The authors
concluded from their results that there was no relationship between hematologic response
and telomere length with response rates to IST. Multivariate analyses did demonstrate that
shorter telomere length was associated with relapse, clonal evolution and mortality. OS for

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the quartile with shortest telomeres was 66% (95% CI: 52.982.5%) surviving 6 years
whereas the remaining, longer telomere patients had an OS of 83.8% (95% CI: 77.390.9%).
Those with the shortest telomere length also had a higher likelihood of progressing to
monosomy 7 [70].

High-dose CY

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Considering the rates of relapse and secondary clonal disease following ATG/CsA [7173],
a need for better nontransplant approaches persists. Reports of autologous hematopoietic
reconstitution with durable remissions in SAA patients after allogeneic BMT following
high-dose CY conditioning suggest that high-dose CY alone is capable of treating the
disease [7476]. In 1976, a case report in the New England Journal of Medicine described a
patient with AA successfully treated with high-dose CY without BMT [77]. The first
published series of high-dose CY therapy for SAA was published in 1996 [74]. This pilot
study included just ten patients, but durable complete remissions were achieved by seven
patients. One of the complete responders died from acquired immunodeficiency syndrome
44 months after treatment with high-dose CY. The six remaining patients are alive and in
continuous complete remission, with a median follow-up of 10.8 years (range: 7.317.8
years) at the time of publication. Enthusiasm for the high-dose CY approach was tempered
by a randomized controlled trial at the NIH comparing high-dose CY/CsA with ATG/CsA.
The study was terminated after enroll- ing just 31 patients over a period of 3 years because
of greater toxicity in the CY/CsA arm, despite the fact that none of the stopping rules or
primary or secondary end points were reached. Only 13 patients in the CY/CsA arm and 12
patients in the ATG/CsA arm were evaluable at 6 months. The 6-month mortality in the CY
plus CsA arm (three out of 13 patients) was not significantly different from the mortality in
the ATG arm (one out of 12 patients; p = 0.3%). No actuarial data or data beyond 6 months
were presented. However, the report did document five relapses and one case of MDS in the
ATG arm, compared with just one relapse in the CY arm. Although the study clearly shows
slower hematopoietic recovery and greater need for blood products and antibiotics in the
CY/CsA arm, the other end points of the study (response rate, response duration, OS and
evolution to secondary clonal disease) were not evaluated [78]. The Johns Hopkins group
recently updated their experience of high-dose CY in 67 additional patients with SAA [76];
44 of these patients had not received prior IST (treatment naive) and 23 had previously
received one or more immunosuppressive regimens (refractory). The trial also employed the
use of G-CSF. At 10 years, the overall actuarial survival was 88%, the response rate was
71%, with the majority being complete, and the actuarial event-free survival (where death,
relapse, MDS, BMT and PNH requiring treatment are defined as events) was 58% in 44
treatment naive SAA patients (Figure 1). Patients with refractory SAA fared less well after
high-dose CY therapy; at 10 years, overall actuarial survival, response and actuarial eventfree survival rates were 62, 48 and 27%, respectively. For treatment-naive patients, the
median time to a neutrophil count of 0.5 109/l was 60 days (range: 28104) and the
median time to last platelet transfusion was 117 days (range: 24640 days). The median time
to a neutrophil count of 0.5 109/l was 54 days (range: 35119 days) and the median time
to last platelet transfusion was 103 days (range: 51751 days) for patients with refractory
SAA. The median time to complete remission was 20 months (range: 470 days). The data
demonstrate that high-dose CY is an effective and potentially curative therapy for patients
with treatment-naive SAA. Early deaths secondary to invasive fungal infection are no higher
after high-dose CY than those reported after ATG/CsA. Relapse and secondary clonal
disease may occur in a minority of patients, but approximately 60% of patients achieve
durable hematopoietic recovery and do not require further immunosuppressive agents. Highdose CY is less effective for patients with refractory SAA, but durable responses occur in
approximately a quarter of these patients.

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Expert commentary
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With modern therapies, the 5-year survival rate for SAA exceeds 85%. BMT offers the best
chance for cure, but its use is restricted by the relatively high morbidity and mortality,
especially in older patients and those who lack an HLA-matched sibling donor. IST remains
the standard of care and leads to meaningful remissions in up to 75% of patients, but the
high rate of relapse and secondary clonal diseases makes this therapy less attractive,
especially for young patients with SAA. Unfortunately, the addition of newer IST (e.g.,
MMF and sirolimus among others) to ATG/CsA does not seem to improve response or
decrease the risk of relapse or clonal disease. High-dose CY therapy seems to produce
higher quality remissions with fewer relapses, but this has not been confirmed in
randomized controlled trials. For first-line therapy, patients should be made aware of the
greater experience with IST when choosing between IST and high-dose CY for first-line
therapy. Although supportive care has greatly improved with antifungal therapy, we seem to
have reached a plateau in the effectiveness of IST. Therefore, in order to improve outcomes
for patients with SAA, there is a need for either improved IST that results in fewer relapses
or less toxic BMT therapies that mitigate graft failure and GVHD, especially when using
alternative donors.

Five-year view
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Currently, advances in mitigating graft failure and GVHD in the setting of alternative donor
BMT appear to be outpacing the development of more effective IST therapies for SAA.
Over the next 5 years there is likely to be great use of unrelated and HLA-mismatched BMT
to treat SAA, especially in patients who do not respond or relapse after IST. The
development of post-transplant CY to expand the donor pool and mitigate GVHD is
especially promising.

Acknowledgments
This work was supported, in part, by grants from the NIH: P01 CA70970 (Robert A Brodsky) and 5K12
HL087169-05 (Amy E DeZern).

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Papers of special note have been highlighted as:
of interest
of considerable interest

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75. Brodsky RA, Sensenbrenner LL, Smith BD, et al. Durable treatment-free remission following
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Box 1

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Aplastic anemia: definitions and diagnosis

Severe AA

Any two of three required for diagnosis

Absolute neutrophil count <500/mm3
Platelets <20,000/mm3
Reticulocyte count <1.0% corrected or <60,000/mm3

Very severe AA

Meets criteria for severe disease and absolute neutrophil count <200/mm3

Non-severe AA

Does not meet criteria for severe AA

AA: Aplastic anemia.

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Key issues

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Ensuring that alternative diagnoses have been eliminated prior to beginning

therapy for severe anaplastic anemia is important.

In children and young adults, it is important to rule out congenital bone marrow
failure syndromes.

In older adults, alternative causes of the bone marrow failure syndrome can be
hypoplastic myelodysplastic syndrome and paroxysmal nocturnal
hemoglobinuria. It is also important to distinguish between them.

It is crucial to initiate early supportive care in severe anaplastic anemia.

It is important to use irradiated blood products and avoid transfusions from

potential bone marrow donors.

Early consideration of bone marrow transplantation in younger patients with a

matched sibling donor is a significant part of the therapeutic process.

If a patient is not a suitable bone marrow transplant candidate, the physician

should use immunosuppressive therapies such as anti-thymocyte globulin/
cyclosporine A or high-dose cyclophosphamide.

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Figure 1. Results of high-dose cyclophosphamide therapy for severe aplastic anemia

(A) Overall survival after high-dose cyclophosphamide therapy for 44 treatment-naive

patients (upper line) and 23 patients refractory to prior immunosuppressive therapy (lower
line), p = 0.03 (log rank test). (B) Failure-free survival after high-dose cyclophosphamide
therapy for 44 treatment-naive patients (upper line) and 23 patients refractory to prior
immunosuppressive therapy (lower line), p = 0.07 (log rank test). This research was
originally published in [76]. The American Society of Hematology.

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