Penugasan - Diagnosis and Treatment of Aplastic Anemia

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Curr Treat Options Oncol. Author manuscript; available in PMC 2018 November 16.
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Published in final edited form as:

Curr Treat Options Oncol. ; 18(12): 70. doi:10.1007/s11864-017-0511-z.
Diagnosis and Treatment of Aplastic Anemia

Scott A. Peslak, MD, PhD1, Timothy Olson, MD, PhD2,3, and Daria V. Babushok, MD, PhD1,2
1Division
of Hematology and Oncology, Department of Medicine, Hospital of the University of
Pennsylvania, Perelman Center for Advanced Medicine, 3400 Civic Center Blvd, Philadelphia, PA
19406, USA
2Comprehensive Bone Marrow Failure Center, Children’s Hospital of Philadelphia, 3615 Civic
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Center Boulevard, Philadelphia, PA 19104

3Division
of Oncology, Department of Pediatrics, Children’s Hospital of Philadelphia, 3615 Civic
Center Boulevard, Philadelphia, PA 19104
Opinion Statement
Acquired aplastic anemia (AA) is a rare, life-threatening bone marrow failure (BMF) disorder that
affects patients of all ages and is caused by lymphocyte destruction of early hematopoietic cells.
Diagnosis of AA requires a comprehensive approach with prompt evaluation for inherited and
secondary causes of bone marrow aplasia, while providing aggressive supportive care. The choice
of frontline therapy is determined by a number of factors including AA severity, age of the patient,
donor availability, and access to optimal therapies. For newly diagnosed severe aplastic anemia,
bone marrow transplant should be pursued in all pediatric patients and in younger adult patients
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when a matched sibling donor is available. Frontline therapy in older adult patients and in all
patients lacking a matched sibling donor involves immunosuppressive therapy (IST) with horse
antithymocyte globulin and cyclosporine A. Recent improvements in upfront therapy include
encouraging results with upfront closely matched unrelated donor transplants in younger patients
and the emerging benefits of eltrombopag combined with initial IST, with randomized studies
underway. In the refractory setting, several therapeutic options exist, with improving outcomes of
matched unrelated donor and haploidentical bone marrow transplantation as well as the addition of
eltrombopag to the non-transplant AA armamentarium. With the recent appreciation of frequent
clonal hematopoiesis in AA patients and with the growing use of next-generation sequencing in
the clinic, utmost caution should be exercised in interpreting the significance of somatic mutations
in AA. Future longitudinal studies of large numbers of patients are needed to determine the
prognostic significance of somatic mutations and to guide optimal surveillance and treatment
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approaches to prevent long term clonal complications.
Corresponding Author: Daria Babushok, M.D. Ph.D., Division of Hematology-Oncology, Department of Medicine, Hospital of the
University of Pennsylvania, Philadelphia, Pennsylvania, PCAM 12 South, 3400 Civic Center Blvd, Philadelphia PA 19104,
[email protected], Phone: 215-614-1847, Fax: 215-615-5888.
Compliance with Ethics Guidelines
Conflict of Interest
The authors have no conflicts of interests to disclose.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Peslak et al. Page 2
Keywords
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Aplastic anemia; bone marrow failure; eltrombopag; cyclosporine A; antithymocyte globulin;

immunosuppressive therapy; bone marrow transplant; clonal hematopoiesis
Introduction
Aplastic anemia (AA) is a rare, immune-mediated hematopoietic disorder associated with
significant morbidity and mortality. In patients with suspected AA, rapid and accurate
diagnosis and concomitant supportive care are critical. Historically, immunosuppressive
therapy (IST) and bone marrow transplantation (BMT) in eligible patients have been the
mainstay of AA treatment [1]. However, new frontline and salvage therapies are
fundamentally changing how we approach therapy of AA, particularly in adult patients [2–
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4]. In pediatric patients, new transplant strategies and improvements in supportive care have
led to greatly improved outcomes and increasing use of BMT in both upfront and refractory
settings [5]. Furthermore, recent recognition of frequent clonal hematopoiesis in AA has
changed our understanding of this immune-mediated blood disorder, reframing how we view
somatic changes and a diagnosis of myelodysplastic syndrome (MDS) in patients with AA
[6, 7]. Here, we present a comprehensive review of the diagnosis and treatment of AA,
focusing on recent studies.
Clinical presentation and epidemiology

AA should be suspected in patients presenting with pancytopenia and a hypocellular bone
marrow. Typical symptoms include fatigue and easy bruising or bleeding; infections may be
present, but generally there is no long-standing illness. There is a well-recognized bimodal
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age distribution with one peak in mid to late childhood and another in the elderly [8]. The
estimated annual incidence of AA is ~2 cases per million in Europe and North America,
with a 2–3 fold higher incidence in East Asia [8]. In ~10% of patients, a history of non-viral
hepatitis can precede the onset of AA [9]; an uncommon association with eosinophilic
fasciitis has also been reported [10]. With rare exceptions, such as chloramphenicol,
antiepileptics, and the emerging link to immunotherapies [8, 11], a causal relationship to
medications or toxins can be difficult to establish.
Diagnosis and severity stratification

When AA is suspected, a comprehensive evaluation should be performed rapidly to exclude
other mimicking conditions (Figure 1, Table 1). A baseline evaluation requires a full history
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and physical exam, a complete blood count with differential, a blood smear, a reticulocyte
count, and a bone marrow aspirate with a core biopsy, with ancillary studies including
cytogenetics and fluorescence in situ hybridization (FISH).
The search for alternative etiologies (Figure 1, Table 1) should focus on ascertainment of
drug and toxin exposures, signs and symptoms suggestive of autoimmune or rheumatologic
diseases, family and/or personal history suggestive of an inherited BMF disorder, infections,
and nutritional deficiencies. Exclusion of inherited BMF is particularly relevant in children
and younger adults, where, at a minimum, an evaluation should include a detailed family
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history looking for lifelong cytopenias, congenital anomalies, cancers, and lung and liver
pathology; in addition, patients should be screened for Fanconi anemia by testing the
patient’s lymphocytes for sensitivity to crosslinking agents and for Dyskeratosis congenita
by measuring lymphocyte telomere lengths [12]. Lymphocyte telomere lengths may also be
low in AA, particularly hepatitis-associated AA, requiring careful interpretation [13].
Additional causes of acquired BMF include autoimmune marrow aplasia due to a clonal T-
or NK- large granular lymphocyte (LGL) expansion [14], which can be evaluated by T cell
receptor rearrangement studies paired with lymphocyte flow cytometry. Morphologic and
cytogenetic analyses are used to evaluate for hypoplastic MDS [15], although limited
cellularity frequently precludes informative morphology assessment. Because of their
association with acquired AA, detection of a paroxysmal nocturnal hemoglobinuria (PNH)
clone (seen in up to 50% of AA patients) or copy number-neutral loss of heterozygosity of
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chromosome arm 6p (6p CN-LOH, seen in about 12% of AA patients) can be helpful in
supporting the diagnosis of AA.
Once the diagnostic evaluation is complete, treatment is guided by the AA severity,

established by the Camitta criteria (Figure 1) [16, 17]. For younger patients with severe
aplastic anemia (SAA) or very severe aplastic anemia (VSAA), a transplant evaluation
should be rapidly initiated. A referral to a tertiary center that specializes in the care of AA
patients should be strongly considered.
Supportive Care
Throughout the diagnostic and treatment process, patients must be provided aggressive
supportive care. Generally, restrictive transfusion targets (hemoglobin > 7 g/dL, platelets >
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10,000 cells/μL) are preferred, especially in potential transplant candidates, given the risk of
alloimmunization and transfusional iron overload [18]. Irradiated blood products should be
used to prevent transfusion-associated graft-versus-host disease (GVHD). Because of the
high mortality due to invasive mold infections, particularly Aspergillus species, antifungal
prophylaxis with voriconazole or posaconazole should be used in patients with severe
neutropenia (absolute neutrophil count < 500 cells/μL) [18]. Pneumocystis jirovecii
pneumonia (PJP) prophylaxis should be used during the period of lymphopenia following
ATG therapy, ideally selecting an alternative to trimethoprim-sulfamethoxazole because of
its myelosuppressive effects. Antimicrobial prophylaxis with quinolone antibiotics in
patients with VSAA can reduce the risk of gram-negative sepsis, but routine use of
prophylactic antibiotics in patients with higher neutrophil counts is not advised in order to
limit antibiotic resistance. Because granulocyte-colony-stimulating factor (G-CSF) does not
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improve overall survival when added to IST [19, 20], routine G-CSF use outside of episodes
of febrile neutropenia remains controversial [21]. The benefits and risks of vaccines in AA
also remain controversial due to the risk of immune activation, with some AA guidelines
recommending against vaccinations outside of the post-transplant setting [21].
Transplant-based therapies for SAA/VSAA

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Patient selection
In patients with SAA and VSAA eligible for transplant-based therapy, age remains the major
factor predicting survival after matched sibling donor (MSD) allogeneic transplantation. A
retrospective analysis from the Center for International Blood and Marrow Transplant
Research (CIBMTR) of over 1,300 patients receiving MSD-BMT showed the adjusted 5-
year overall survival (OS) of 53% in patients over the age of 40 years, as compared to 82%
for patients under 20 years and 72% for patients aged 20–40 years [22]. The differences
were primarily due to increased GVHD, infections, and delayed platelet recovery in the
older cohort. In addition, these patients were more likely to have received prior IST, and/or
to have additional comorbidities with poorer performance status and a longer interval
between diagnosis and BMT [22]. Although outcomes in older patients transplanted with
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fludarabine-containing regimens have been more encouraging, these data are limited to
retrospective analyses [23]. Thus, the current standard of care for patients older than 40
years is frontline IST, while BMT is the treatment of choice for children and young adults
with SAA who have a MSD (Figure 1).
Donor choice
Historically, frontline transplantation for SAA in patients under 40 years of age has been
largely limited to MSD transplants [24, 25]. However, a recent retrospective analysis of
approximately 1,450 patients with AA transplanted between 2005 and 2009 showed no
significant difference in OS between MSD and matched unrelated donor (MUD) transplant,
although rates of acute and chronic GVHD were higher with MUD-BMT [26]. An analysis
of 29 pediatric patients treated with Fludarabine/Cyclophosphamide/ATG (FCC)
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conditioning followed by unrelated donor transplantation showed similar overall and

progression-free survival as compared to historical MSD-BMT controls, and superior
outcomes compared to IST [5], suggesting that front-line therapy with MUD-BMT may be
considered upfront in selected patients under age 20. Randomized trials are underway to
compare outcomes of upfront MUD-BMT versus IST in pediatric patients without a
matched sibling donor (Pediatric Blood and Marrow Transplant Consortium and the North
American Pediatric Aplastic Anemia Consortium); studies exploring frontline MUD-BMT
in adults under 40 are also ongoing (Blood and Marrow Transplant Clinical Trials Network).
Pending these prospective studies, IST remains the standard upfront AA therapy in patients
without MSD [26, 5].
The outcomes of mismatched or haploidentical donor transplantation in AA have also

improved. In a prospective multicenter study of 101 AA patients receiving haploidentical
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transplants in China, 94% of patients achieved successful engraftment with 3-year overall
and failure free survival of 89% and 86%, respectively [27]. A registry-based comparison of
upfront haploidentical and MSD transplantation in 158 consecutive SAA patients in China
have shown similar high rates of engraftment and OS, but significantly higher rates of grade
III–IV acute GVHD (10% versus 1.5%) and chronic GVHD (31% versus 4.4%) for
haploidentical transplants [28]. A more recent study of 16 patients receiving haploidentical
or unrelated donor transplants with post-transplant cyclophosphamide showed encouraging
results with 100% engraftment and no instances of grade 3 or higher GVHD [29]. Novel
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approaches including co-infusion of mesenchymal stem cells [30] and selective T cell
Receptor αβ depletion [31] are being explored.
Graft source
Bone marrow grafts have been shown to produce superior OS compared to peripheral blood
stem cell (PBSC) grafts in both pediatric [32] and adult [33] AA patients, due to lower rates
of GVHD. More recent efforts to improve outcomes with PBSC showed encouraging results
with partial T cell depletion [34]; larger randomized prospective studies are needed to
confirm the efficacy and safety of this approach.
Conditioning Regimens
The standard conditioning regimen for MSD-BMT in younger patients is 200 mg/kg
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cyclophosphamide with antithymocyte globulin (ATG), with three-year survival rates of 92%
[35]. However, subsequent studies in older transplant recipients (age > 30) did not show a
survival benefit when compared to IST [36]. To reduce toxicity in older patients, newer
regimens have incorporated fludarabine with lower-dose cyclophosphamide and with ATG
(FCA) or alemtuzumab (FCC), with improved OS [37–39]. A CIBMTR analysis of 833 AA
bone marrow transplants evaluated the role of ATG source on transplant outcomes, and
demonstrated that rabbit ATG (Thymoglobulin, Sanofi, France) results in lower rates of
acute and chronic GVHD for MSD transplants, improves survival, and lowers rates of acute
GVHD for MUD transplants [40]. Conditioning for MUD and haploidentical transplants
also includes 200 cGy total body irradiation [41].
Non-transplant therapy of AA
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Immunosuppression
For patients older than 40 years with newly-diagnosed SAA/VSAA or younger patients
without an MSD, immunosuppression with ATG and cyclosporine A (CsA) continues to be
the recommended frontline therapy (Figure 1) [42], offering outcomes comparable to
allogeneic BMT with reduced morbidity in older patients [43, 44]. Horse ATG is the
recommended ATG source, based on a randomized-controlled trial of 120 patients showing a
superior overall response (68% compared to 37%) and OS (96% compared to 76%) for horse
ATG-based IST compared to rabbit ATG-based IST [45].
Role of Eltrombopag in Frontline Therapy

One of the most promising recent treatments for AA is the oral thrombopoietin (TPO)
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receptor agonist eltrombopag, previously approved for treatment of chronic idiopathic

thrombocytopenic purpura [46]. Studies in mouse models showed that signaling via the TPO
receptor c-mpl is necessary for hematopoietic stem cell maintenance and downstream
expansion and differentiation [47, 48]. Interestingly, patients with congenital
amegakaryocytic thrombocytopenia who have mutations in c-mpl can progress to aplastic
anemia, suggesting that a deficiency in TPO signaling may play a role in AA pathogenesis
[49]. Based on these studies, eltrombopag was initially tested as monotherapy in a Phase 2
study of 43 patients with relapsed/refractory SAA with persistent thrombocytopenia
following IST [2, 3]. The overall response rate after 3–4 months of therapy was 40% (17 of
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43). Remarkably, one patient achieved a trilineage response, and 8 patients had neutrophil
responses including 4 with severe neutropenia. With long-term treatment, 7 patients
achieved trilineage responses. An early signal of increased clonal evolution in this high-risk
population was also noted with 19% (8 of 43) patients developing cytogenetic abnormalities
during follow-up [2, 3].
Based on these encouraging data, a phase 1/2 study evaluated whether the addition of
eltrombopag to frontline IST can further improve patient outcomes [4]. 92 patients were
assigned to receive daily eltrombopag in addition to horse ATG and CsA in three separate
cohorts starting eltrombopag at either day 0 or day 14 and continuing for 3 or 6 months.
Because of the concern for karyotypic evolution [2, 3], patients with cytogenetic
abnormalities were excluded. The overall response rate at 6 months in the three cohorts
ranged between 80–94%, as compared to 66% in the composite historical cohort of 102
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patients [50, 45]. There was also an encouraging improvement in the rate of complete
response, at 36% with eltrombopag as compared to a historical estimate of 10% with
standard IST. During an initial phase of the study CsA was discontinued at 6 months, with a
relapse rate of 32%–54%, leading to a protocol amendment to extend CsA duration to 2
years [4]. Encouragingly, the rates of chromosomal aberrations were similar to those in
historical controls, ~8% at 2 years of follow-up [4]. Several prospective randomized trials
combining eltrombopag therapy with IST are underway to confirm these findings and to
better assess long-term efficacy and safety, particularly clonal evolution (Table 2). However,
given these encouraging early results and low observed toxicity, we believe that in selected
newly diagnosed SAA/VSAA patients without pre-existing karyotypic abnormalities,
addition of six months of eltrombopag to upfront standard IST should be considered.
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Cyclosporine Maintenance and Taper

Although there are no definitive data on the optimal duration of CsA, it is clear that early
discontinuation leads to a high rate of early relapse. An 11-year follow-up of a randomized
trial of horse ATG with or without CsA showed that CsA maintenance delays relapses. 26%
of patients required CsA for greater than 6 months due to recurrent cytopenias on
discontinuation [43]. Follow-up of two National Institutes of Health cohorts totaling 102
patients treated with standard IST for whom CsA taper was started at 6 months showed a
cumulative relapse rate of 33% at 5 years of follow-up, with a median time to relapse of 2
years [51]. Compared to historical cohorts that discontinued CsA at 6 months, a tapering
regimen delayed relapse by approximately 1 year [51]. The high relapse rates of 32%–54%
in the recent study of eltrombopag added to upfront IST were also attributed to early CsA
discontinuation, and were improved with extending CsA to a 2 year maintenance [4]. There
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are limited data on the rate of CsA taper, although an analysis of 33 pediatric AA patients
suggested that a slower taper of <0.3mg/kg/month may lead to fewer relapses [52]. Putting
these data together, our practice (Figure 1) is to continue full dose CsA, targeting therapeutic
CsA trough of 200–300 mcg/L, for approximately 12 months after horse ATG therapy and
until achievement of stable and maximally-improved blood counts, at which time we initiate
a slow taper with no more than 10% dose reduction at a time over the course of
approximately one year.
Treatment of nonsevere aplastic anemia (NSAA)

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Unlike the fairly defined guidelines for frontline treatment of SAA/VSAA (Figure 1), the
approach to nonsevere aplastic anemia (NSAA) is more nuanced. The natural history of
patients with NSAA has been evaluated in several retrospective analyses, showing
progression of cytopenias in ~20–67% of NSAA patients [53–56]. Interestingly, NSAA
patients managed in more recent years (1997–2002) appear to have worse outcomes with a
56% 10-year survival as compared to 70% in NSAA patients treated between 1991–1996;
this was associated with a significantly longer interval from diagnosis to treatment in the
more recent cohort (52 versus 102 days) [57]. Expert AA guidelines recommend treating
NSAA patients if they have transfusion dependence or neutropenia [21]. A prospective
randomized study compared horse ATG and CsA to CsA monotherapy in 114 NSAA
patients, showing significantly higher overall response (74% versus 46%) in the ATG and
CsA arm [58]. Transfusion independence was achieved in 90% of ATG/CsA-treated patients
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compared to only 67% of patients receiving CsA alone; 5-year OS was equivalent in both
groups [58]. The outcomes of a recent cohort of 95 Japanese NSAA patients treated with
horse ATG and CsA were less encouraging, showing a lower 6-month response rate of 55%
and a 10-year failure free survival of 44%, with the majority of patients needing second- and
third-line therapies. The median time to initial treatment was 47 days [59].
More recently, eltrombopag has been proposed as a potential option for NSAA patients, with
a number of ongoing studies studying the safety and efficacy of eltrombopag in combination
with CsA in NSAA (Table 2) [60]. Given the excellent tolerability and efficacy of
eltrombopag in the relapsed/refractory and first-line SAA/VSAA settings (Table 2) [2–4],
we anticipate that eltrombopag-containing regimens would be similarly beneficial in NSAA
and may allow for improved outcomes with lower toxicities in this population.
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Several other treatments have been investigated in NSAA; however, to date, none have been
demonstrated to be superior to standard IST. In 45 patients with NSAA treated with a
recombinant humanized anti-IL2 receptor antibody daclizumab, 42% achieved a
hematologic response at 3 months [61], although only 25% achieved transfusion
independence at ~5 years of follow-up [62]. An antihelminthic agent levamisole, associated
with immunomodulatory activity, was tested in combination with CsA in 118 Chinese
patients with NSAA; the study found a nearly 100% overall response rate in 42 patients with
newly-diagnosed NSAA and 87% overall response rate in chronic NSAA [63], suggesting
that CsA combined with levamisole may be a promising therapy to be evaluated in future
randomized studies.
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Clonal evolution
The improvement in long-term survival of AA patients led to an increased appreciation of
the long-term clonal sequelae of AA. ~15% of AA patients treated with IST go on to
develop the late complications of MDS and acute myeloid leukemia (AML) [64, 65, 43].
Approximately 10% of AA patients (range 3–26%) develop cytogenetic changes during the
course of their disease (reviewed in [7]), most commonly monosomy 7/del (7q) and trisomy
8, as well as del (13q), and trisomies of chromosomes 6, 15 and 21. In the context of AA,
monosomy 7 has been found to correlate with a poor prognosis, including a worse response
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to IST and increased progression to MDS, while del (13q) and trisomy 8 are associated with
an improved response to IST and a better prognosis (reviewed in [6, 7]).
Newer techniques combining single nucleotide polymorphism arrays (SNP-A) and next-
generation sequencing (NGS) have allowed to more precisely evaluate clonal hematopoiesis
in AA. The majority of AA patients, including over 60% of children with AA, develop
clonal genetic changes [66, 67]. Several recent reviews comprehensively addressed this topic
[6, 7, 68]. The most common clonal abnormality in AA is the development of PNH clones,
which can be detected by flow cytometry as cells lacking glycophophatidyl-inositol-linked
proteins due to a somatic mutation in the PIGA gene [69, 70], found in up to 50% of AA
patients. The second most common is somatic loss of human leukocyte antigen (HLA) loci,
that are detected as either regions of acquired 6p CN-LOH or as inactivating mutations in
HLA class I genes in approximately 17% of AA patients [71–74]. Both PNH clones and
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HLA loss are hypothesized to occur due to immune escape, and, if present, can be helpful in
corroborating a diagnosis of AA. The presence of even a subclinical PNH clone has been
found to correlate with an improved response to IST [75–79, 70]. In contrast to PNH, the
prognostic impact of somatic HLA loss is less clear [71, 72], with emerging data suggesting
that HLA loss may be best viewed as a marker of a higher immune pathogenicity of a
patient’s inherited HLA alleles [74, 73].
Using targeted NGS of genes recurrently mutated in hematologic malignancies, several

groups identified somatic mutations in MDS-associated genes in AA, detected in up to a
third of adult AA patients [80–83, 66]. The most commonly mutated malignancy-associated
genes in AA are ASXL1, BCOR/BCORL1, and DNMT3A [66, 81, 82]. The prognostic
implications of somatic mutations in MDS-associated genes are not clear, due to the lack of
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prospective, long-term studies of large numbers of patients carrying these mutations.

Nevertheless, available data suggest that mutations in BCOR and BCORL1 may be
predictive of an improved response to IST [66], and together with mutations in PIGA,
comprise a group with “favorable” prognosis [66]. In the comprehensive study of clonal
hematopoiesis in AA by Yoshizato and colleagues, no other genes were identified to have
prognostic significance individually, perhaps due to the limited statistical power, although
several genes (DNMT3A, ASXL1, TP53, RUNX1, and CSMD1) were associated with
worse OS when analyzed in aggregate [66]. Putting together the available data, it is clear
that the majority of pediatric and adult AA patients develop clonal hematopoiesis, with a
large fraction of adult AA patients having detectable somatic mutations in genes that are
frequently altered in aging and MDS. However, only ~15% of AA patients progress to the
late complications of MDS and leukemia after 10 years of follow-up [64]. Thus, in the
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absence of prospective longitudinal studies evaluating the prognosis of AA patients carrying

specific MDS-associated somatic mutations, we advise caution when factoring the presence
of somatic mutations into therapeutic decisions in this patient population.
Salvage therapy for relapsed and refractory aplastic anemia

Despite overall improvement in AA outcomes, ~33–35% of patients who initially respond to
IST will relapse during or after CsA taper, while another 35% will be refractory to frontline
IST [45, 1]. Most patients (~60–68%) who relapse following an initial response to IST can
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be salvaged with full-dose CsA monotherapy and/or a second course of IST with rabbit ATG
and CsA [84, 52, 85, 42, 86] or transplant. Alternatives to ATG and CsA in relapsed disease
include alemtuzumab, which, in a single-arm prospective study of 25 patients with relapsed
AA, was shown to produce a hematologic response in 56% of patients, with 86% 3-year
survival [87]. Because most patients will respond to a second round of IST [84], in adults,
transplant therapies are usually reserved for relapsed patients who failed an attempt of
salvage with a second course of immunosuppression, while excellent outcomes in children
with salvage BMT after IST failure make MUD-BMT a reasonable second-line option [88].
Compared to relapsed AA patients who previously responded to IST, patients with primary
refractory AA have worse outcomes, and only ~30% of refractory AA patients can be
salvaged with rabbit ATG and CsA [84]. The failure-free survival in refractory pediatric
patients treated with second-line IST can be as poor as 9.5%, as compared to >80% for
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salvage SCT [89]. Thus, refractory AA patients should be evaluated for salvage allogeneic
transplant options, which may include HLA identical sibling, matched unrelated, or
haploidentical bone marrow transplantation, depending on donor availability. Among non-
transplant therapies, eltrombopag has hematologic response rates of ~40% in refractory AA,
including some trilineage responses, and represents an important option, particularly for
older adults or patients who are poor transplant candidates [2, 3].
There are several additional second- and third-line treatment options for refractory AA, of
which danazol and alemtuzumab are more commonly used. In 48 patients with refractory
AA randomized to receive alemtuzumab versus rabbit ATG with CsA, alemtuzumab was
comparable to rabbit ATG arm, with a hematologic response of 37% and a 3-year survival of
83% [87]. Although androgen therapy has not been found to improve survival in
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combination with first-line IST [90, 91], a study of 16 refractory AA patients suggests that
androgens may be helpful, particularly in female patients [92]. Cyclophosphamide in
moderate to high doses also has efficacy in refractory AA [93–95], but significant toxicity
with prolonged neutropenia and high rates of infectious have largely limited its use [96, 97].
Summary
AA is a rare, life-threatening, BMF syndrome that requires a systematic and timely approach
to diagnosis and treatment. For a younger patient with a MSD, allogeneic BMT remains the
standard frontline therapy, while other patients should receive frontline immunosuppression
with horse ATG and CsA. Emerging data suggest that addition of eltrombopag to frontline
IST can further improve outcomes and that outcomes following upfront MUD BMT may
now be equivalent to MSD-BMT, at least in pediatric patients. Long-term prospective studies
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are underway to confirm the safety and efficacy of these approaches. As the outcomes of
MUD and haploidentical transplantation improve and with emergence of eltrombopag as an
effective agent in refractory AA, we expect that outcomes of patients with refractory AA
will improve. Finally, with the recent findings of frequent clonal hematopoiesis in the
majority of AA patients, utmost caution should be exercised in the interpretation of
molecular changes which are common in this patient population and, in the absence of long-
term prospective studies, do not have well-defined prognostic implications.
Acknowledgments
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This work was supported by NHLBI T32 HL007439-38 grant to S.A.P, NHLBI K08 HL122306 to T.O., and
NHLBI K08 HL132101-01 and AA & MDS International Foundation Research Grant to D.V.B, and and NIH/
NIDDK R24DK103001 for Penn/CHOP AA studies.
References and Recommended Reading

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98. [Internet] Cg. Eltrombopag Combined With Cyclosporine as First Line Therapy in Patients With
Severe Acquired Aplastic Anemia (SOAR). 10 May 2017. Bethesda (MD): National Library of
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Bethesda (MD): National Library of Medicine;
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Figure 1. Approach to diagnosis and treatment of acquired aplastic anemia

Initial screening evaluation of a patient with aplastic anemia is required to document
pancytopenia with a hypocellular marrow, followed by testing to exclude alternative
diagnoses. Aplastic anemia severity and outcomes of a transplant evaluation factor into
determining an optimal treatment strategy. Patients with Severe or Very Severe Aplastic
Anemia (SAA/VSAA) 40 years of age or younger with an HLA-matched sibling donor
should undergo an evaluation for an allogeneic bone marrow transplant; older patients or
Author Manuscript
patients without an HLA-identical sibling donor should be evaluated for frontline

immunosuppressive therapy (IST) with horse ATG and CsA. **Based on recent data
showing superior hematologic outcomes with the addition of eltrombopag [4], addition of 6
months of eltrombopag to standard IST in patients without pre-existing cytogenetic
abnormalities can be considered. Cyclosporine A should be continued for ~12 months of
therapy, followed by a slow taper to reduce relapse rates. Salvage therapies include
alternative transplant modalities and a variety of nontransplant options. AA, aplastic anemia;
PNH, paroxysmal nocturnal hemoglobinuria; 6p CN-LOH, copy number-neutral loss of

Author Manuscript
heterozygosity of chromosome arm 6p; alloSCT, allogeneic stem cell transplant; NSAA,
nonsevere aplastic anemia; SAA, severe aplastic anemia; VSAA, very severe aplastic
anemia. *Cellularity criteria are determined on adequate bone marrow biopsy, and
hypoplastic marrow can either be diagnosed on total cellularity or on bone marrow biopsy
with <50 percent normal cellularity in which < 30 percent of the cells are hematopoietic.
HLA, human leukocyte antigen; alloBMT, allogeneic bone marrow transplant; IST,
immunosuppressive therapy; hATG, horse antithymocyte globulin; CsA, cyclosporine A;
CR, complete response; PR, partial response; Cy, cyclophosphamide; MRD, matched related
donor; MUD, matched unrelated donor; haplo BMT, haploidentical bone marrow transplant.
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Table 1
Diagnostic evaluation of a patient with suspected acquired aplastic anemia
A variety of testing modalities in addition to a detailed personal/family history and exposure history are required both in the initial screening evaluation as
well as the subsequent exclusion of alternative diagnoses.
Peslak et al.
Initial screening evaluation

Peripheral blood CBC with differential, peripheral blood smear, reticulocyte count
Complete metabolic panel, LDH, haptoglobin, coagulation parameters
Bone marrow aspirate and biopsy with Bone marrow aspirate and biopsy
ancillary studies Metaphase cytogenetics and FISH panel for MDS-associated chromosomal abnormalities of chromosomes 5, 7, 8, 20
* Molecular studies
Exclusion of alternative diagnoses

Infectious HIV, Hepatitis B/C, parvovirus B19 PCR, EBV, CMV, bacterial, fungal (+/− mycobacterial testing)
Inherited bone marrow failure Detailed family history focusing on cytopenias, congenital abnormalities, cancers and lung and liver pathology
Chromosomal breakage testing for Fanconi anemia
Lymphocyte telomere length for Dyskeratosis congenita
Additional syndrome-specific testing if personal or family history are suggestive of specific disorders (IBMF, HLH)
Lymphoproliferative Flow cytometry and T-cell receptor rearrangement testing for clonal LGL expansion
Medication or toxin-related Detailed drug and occupational exposure history, with attention to excessive alcohol intake, antibiotics, prior cytotoxic chemotherapeutic agents, and
immune-activating agents (e.g. interferon and checkpoint blockade inhibitors)
Nutritional Vitamin B12, folate, copper, iron studies, ferritin
Rheumatologic Antinuclear antibody, rheumatoid factor, erythrocyte sedimentation rate, C-reactive protein
Others (rare) Exclude other rare etiologies of pancytopenia with a hypocellular marrow: e.g. graft-versus-host disease, HLH
CBC, complete blood count; LDH, lactate dehydrogenase; MPN myeloproliferative neoplasm; FISH, fluorescence in-situ hybridization; MDS, myelodysplastic syndrome; HIV, human immunodeficiency
virus; EBV, Epstein-Barr virus; CMV, cytomegalovirus; DEB, diepoxybutane; SLE, systemic lupus erythematosus; RA, rheumatoid arthritis; IBMF, inherited bone marrow failure; HLH, hemophagocytic
lymphohistiocytosis; LGL, large granular lymphocyte.
*
Although in current clinical practice molecular sequencing panels of somatic mutations in hematologic malignancy-associated genes are frequently included and can provide useful supporting information,
in isolation, presence of somatic mutations in patients with AA should be interpreted with caution due to their high frequency in this patient population and uncertain prognostic significance (see text).
Page 20
Table 2
Eltrombopag in the treatment of aplastic anemia.
Type of study Inclusion/Exclusion Patients, n Median Treatment arms Duration of Follow-up Outcomes Clonal Evolution
age, yrs
Peslak et al.
(range)
Townsley et Phase 1/2 Inclusion: 92 32 (3–82) hATG/CsA + eltrombopag Up to 24 months Eltrombopag + 7/92 (7.6%)
al. (2017) [4] Age >2 with previously hATG/CsA developed clonal
untreated SAA showed ORR of abnormalities on
Exclusion: 80% and CR of cytogenetics
FA, liver impairment, or 36%, improved
abnormal cytogenetics from historical
cohorts with ORR
66%, CR 10%
SOAR trial Phase 2 Inclusion 50 (target) N/A CsA +/− eltrombopag Planned for up to 60 Pending trial; Planned evaluation
(pending) Age ≥6 with SAA months primary end point for clonal evolution
[98] Exclusion: hematologic to PNH, MDS, or
Prior CsA, alemtuzumab, response at 6 acute leukemia
ATG, or TPO-R agonists; months
diagnosis of FA or
abnormal cytogenetics
EBMT-SAA Phase 3 Inclusion: 200 (target) N/A hATG/CsA +/− eltrombopag Planned for at least 2 Pending trial; Planned evaluation
Working Age >14 with SAA/ years primary end point for clonal evolution
Party RACE VSAA complete response to PNH or clonal
trial Exclusion: at 3 months cytogenetics
(pending) Prior ATG; diagnosis of
[99] FA, DC, or MDS
Höchsmann Phase 2/3 Inclusion: 29 (target) N/A CsA +/− eltrombopag Planned for 6 months Pending trial; Planned evaluation
et al. EMAA Age ≥ 2 with NSAA or after last dose primary end point for clonal evolution
trial unilineage BMF; PLT eltrombopag hematologic to PNH or clonal
(pending) transfusion dependent response at 6 cytogenetics
[60] Exclusion: months
ATG therapy in prior 6
months; diagnosis of FA
Olnes et al. Phase 2 with Inclusion: 43 44 (17–77) Eltrombopag Up to 4 years follow up ORR at 3–4 8/43 patients
(2012) extension Age >12 years with SAA months of 40% (18.6%) developed
Desmond et refractory to ≥1 IST (17/43), including clonal abnormalities
al. (2014) [2, regimen; PLT <30K/uL 1 patient with on cytogenetics
3] Exclusion: trilineage
Diagnosis of FA, familial response, 9
marrow failure, or DC patients with PLT
transfusion
independence, and
8 patients with
neutrophil
response
SAA, severe aplastic anemia; VSAA, very severe aplastic anemia; NSAA, nonsevere aplastic anemia; PLT, platelet; ORR, overall response rate; CR, complete response; FA, Fanconi anemia; DC,
Dyskeratosis congenita, hATG, horse antithymocyte globulin; CsA, cyclosporine A; IST, immunosuppressive therapy; EMBT-SAA, European Society for Blood and Marrow Transplantation Severe Aplastic
Page 21
Anemia; RACE, Randomized multicenter study comparing horse Antithymocyte globuline (hATG) + Cyclosporine A (CsA) with or without Eltrombopag; EMAA, Efficacy and Safety of Eltrombopag +
CsA in Patients with Moderate Aplastic Anemia; SOAR, Eltrombopag Combined With Cyclosporine as First Line Therapy in Patients With Severe Acquired Aplastic Anemia.
Peslak et al.
Page 22

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Diagnosis and Treatment of Aplastic Anemia

Center Boulevard, Philadelphia, PA 19104

approaches to prevent long term clonal complications.

Aplastic anemia; bone marrow failure; eltrombopag; cyclosporine A; antithymocyte globulin;

Clinical presentation and epidemiology

Diagnosis and severity stratification

Once the diagnostic evaluation is complete, treatment is guided by the AA severity,

Transplant-based therapies for SAA/VSAA

conditioning followed by unrelated donor transplantation showed similar overall and

The outcomes of mismatched or haploidentical donor transplantation in AA have also

Role of Eltrombopag in Frontline Therapy

receptor agonist eltrombopag, previously approved for treatment of chronic idiopathic

Cyclosporine Maintenance and Taper

Treatment of nonsevere aplastic anemia (NSAA)

Using targeted NGS of genes recurrently mutated in hematologic malignancies, several

prospective, long-term studies of large numbers of patients carrying these mutations.

absence of prospective longitudinal studies evaluating the prognosis of AA patients carrying

Salvage therapy for relapsed and refractory aplastic anemia

References and Recommended Reading

10.3109/07853890.2014.915579 [PubMed: 24888387]

2013; 48(2):162–7. DOI: 10.1038/bmt.2012.230 [PubMed: 23165495]

10.3324/haematol.2009.006916 [PubMed: 19734425]

cyclophosphamide dose deescalation study show life-threatening adverse events at predefined

maintenance of normal hematopoiesis in humans: development of aplastic anemia in patients with

Pediatr Hematol Oncol. 2013; 35(2):148–52. DOI: 10.1097/MPH.0b013e3182755f36 [PubMed:

208(4):115–28. DOI: 10.1016/j.cancergen.2015.01.007 [PubMed: 25800665]

2011; 118(25):6601–9. DOI: 10.1182/blood-2011-07-365189 [PubMed: 21963603]

Blood. 2017; 129(21):2908–16. doi:10.1182/blood-2016-11-752378. A flow-cytometric

mutations identify a subgroup of aplastic anemia patients who progress to myelodysplastic

345–54. DOI: 10.1182/blood-2011-05-352328 [PubMed: 22067384]

oxymetholone. Blood. 1992; 79(10):2566–71. [PubMed: 1586708]

Figure 1. Approach to diagnosis and treatment of acquired aplastic anemia

patients without an HLA-identical sibling donor should be evaluated for frontline

PNH, paroxysmal nocturnal hemoglobinuria; 6p CN-LOH, copy number-neutral loss of

Initial screening evaluation

Exclusion of alternative diagnoses

Nutritional Vitamin B12, folate, copper, iron studies, ferritin

Eltrombopag in the treatment of aplastic anemia.

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