Long-Term Outcome of Pediatric Patients with Severe Aplastic Anemia Treated

with Antithymocyte Globulin and Cyclosporine

PHILLIP SCHEINBERG, MD, COLIN O. WU, PHD, OLGA NUNEZ, RN, AND NEAL S. YOUNG, MD

Objective To determine the long-term outcomes in children with severe aplastic anemia (SAA) treated with antithymocyte globulin
(ATG) and cyclosporine (CsA) through a retrospective analysis of the pediatric patients treated at our institution in all protocols that
included horse ATG (h-ATG) and CsA.
Study design Between 1989 and 2006, a total of 406 patients, 20% of whom were children under age 18 years, received an initial
course of immunosuppressive therapy (IST) at our institution. Here we report the outcome of 77 children who were treated with an h-
ATG plus CsA– based regimen during this period.
Results The overall response rate at 6 months was 74% (57/77); the cumulative incidence of relapse at 10 years was 33%, and the
median time to relapse was 558 days. The cumulative incidence of evolution after IST was 8.5%; all 3 such events occurred in partial
responders. Overall, there were 13 deaths (17%), with 4 occurring within the 3 months after IST in patients who had a pretreatment
absolute neutrophil count of < 100/ L and the other 9 occurring more than 6 months after initiation of IST. The median time to death
was 570 days. The overall 10-year survival for the entire cohort was 80%; long-term survival in the children who responded to IST
was 89%.
Conclusions The long-term survival in pediatric patients who respond to IST is excellent, at about 90%. IST remains a good
alternative in pediatric patients who lack an HLA-matched sibling donor and should be offered as initial therapy before possible
hematopoietic stem cell transplantation from an unrelated donor. (J Pediatr 2008;153:814-9)

rom its initial description, aplastic anemia (AA) has been identified as a disease of the young. The age distribution of F affected patients reveals 2
distinct peaks, the first between age 15 and 25 and the second after age 60. Most cases occur in the younger age group.1 AA can be either inherited or
acquired. Historically, patients with an inherited form of AA were identified by characteristic physical findings, such as short stature, abnormal
thumbs, hypopigmentation, and café au lait
spots (Fanconi anemia) or skin pigmentation, nail dystrophy, and oral leukoplakia (dyskeratosis congenita). However, abnormal
physical examination findings may not always be seen in patients with an inherited bone marrow failure syndrome, and the
identification of specific mutations in genes of the telomere complex in patients with
acquired AA has blurred the distinction between the inherited and acquired forms of
2-4
AA.
Although environmental exposure has been linked to the onset of severe AA
(SAA), most cases are idiopathic. Regardless of etiology, patients are treated with either From the Hematology Branch (P.S.,
immu-nosuppressive therapy (IST) or hematopoietic stem cell transplantation (HSCT). In O.N., N.Y.) and Office of Biostatistics
Research (C.W.), National Heart,
general, the outcome after HSCT has been better in children than in adults, with less Lung and Blood Institute, National
5,6
frequent and severe graft-versus-host disease and better overall survival. However, Institutes of Health, Be-thesda, MD.
because most children with SAA lack an HLA-histocompatible sibling, IST is often Supported by the Intramural Research
Pro-gram of the National Institutes of
administered as first therapy. The standard IST regimen is antithymocyte globulin (ATG) Health, National Heart, Lung and Blood
7
plus cyclosporine (CsA). Institute. The authors have no conflicts
of interest to disclose.
Over the past 18 years, we have treated more than 400 patients with newly Submitted for publication Nov 29,
diagnosed SAA with IST, about 20% of whom were under age 18 years. During this 2014; last revision received Apr 30,
2015; ac-cepted Jun 4, 2008.
Reprint requests: Dr Phillip Scheinberg,
Hematology Branch, NHLBI, 10 Center
AA Aplastic anemia CsA Cyclosporine
AD Alternative donor GPI Glycosylphosphatidylinositol Drive, Building 10 CRC, Rm 3-5140,
ALC Absolute lymphocyte count h-ATG Horse antithymocyte globulin MSC 1202, Bethesda, MD 20892-1202.
ANC Absolute neutrophil count HSCT Hematopoietic stem cell transplantation E-mail: scheinbp@mail.nih.gov.
ARC Absolute reticulocyte count IST Immunosuppressive therapy 0022-3476/$ - see front matter
ATG Antithymocyte globulin MMF Mycophenolate mofetil Copyright © 2008 Mosby Inc. All
CI Confidence interval PR Partial response rights reserved.
CR Complete response SAA Severe aplastic anemia
10.1016/j.jpeds.2008.06.004

814
period, 3 horse ATG (h-ATG)– based regimens were studied:
(1) standard h-ATG CsA, (2) h-ATG CsA myco-phenolate
mofetil (MMF), and (3) h-ATG CsA siroli-mus. The outcome
was found to be similar for these 3 h-ATG regimens,
indicating that adding a third immunosuppressive agent to
the standard h-ATG CsA did not alter the response rate or the
8,9
incidence of relapse and evolution. To gain insight into the
long-term outcome of children treated with IST, we
conducted a single-center retrospective analysis of the rates
of response, relapse, clonal evolution, and overall survival in
children with acquired SAA treated with an h-ATG/CsA–
based therapy.
METHODS
All children under age 18 years who fulfilled the entry
criteria for SAA and who did not have an HLA-matched
sibling at the time of study entry were offered enrollment in 1
of 4 different immunosuppression protocols between No-
vember 1989 and December 2006 at the Warren Grant Mag-
nuson Clinical Center and the Mark O. Hatfield Clinical
Research Center at the National Institutes of Health in Be-
thesda, Maryland. Consecutive patients treated in these 4
sequential immunosuppression protocols were analyzed. Pa-
tients who had an HLA-matched sibling but a parent or legal
guardian who opted against initial transplantation also were
offered IST. All patients age 7 years and older signed a minor
assent, and all parents or legal guardians signed informed
consent according to protocols approved by the Institutional
Review Board of the National, Heart, Lung, and Blood
Institute.
For protocol entry purposes, SAA was defined as bone
marrow cellularity 30% and severe pancytopenia with at least
2 of the following peripheral blood count criteria: (1)
absolute neutrophil count (ANC) 500/uL, (2) absolute
reticulocyte count (ARC) 60 000/mL, and (3) platelet count
10
20 000/mL. Response was defined as no longer meeting
the criteria for SAA, as determined at 3 and 6 months after
9,10
ATG therapy. This criterion has been shown to correlate
strongly with both independence from transfusion and
8
survival at 1 year. A complete response (CR) was defined as
satisfaction of all 3 of the following peripheral blood count
criteria: (1) ANC 1000/mL, (2) hemoglobin 10 g/dL, and (3)
platelet count 100 000/mL. A partial response (PR) was
defined as a blood count no longer satisfying the criteria for
SAA but insufficient to fulfill the criteria for CR. Relapse
was defined not based on blood cell counts but rather as any
8
reinstitution of IST.
Bone marrow biopsy and aspiration, including cytoge-
netics, were performed before enrollment. All patients under-
went a chromosome assay after in vitro exposure of lympho-
cytes to diepoxybutane and in some cases also to mitomycin C,
to exclude Fanconi anemia. Testing for paroxysmal noc-turnal
hemoglobinuria was done using the Ham test until the year
11
2000, when it was replaced by a flow cytometric assay.
Long-Term Outcome of Pediatric Patients with Severe Aplastic Anemia Treated with Antithymocyte Globulin and Cyclosporine815
The presence of a clone was defined as the absence of glyco-
sylphosphatidylinositol (GPI)-anchored surface proteins in
1% of neutrophils or red cells; the size of the paroxysmal
nocturnal hemoglobinuria clone was defined by the highest
level of GPI-negative red blood cells or GPI-negative neu-
trophils.
Study Design and Treatment Regimens
An ATG skin test was performed in all patients to
assess for allergic hypersensitivity. H-ATG (ATGAM; Phar-
macia & Upjohn Company, Kalamazoo, Michigan) was ad-
ministered intravenously at a dosage of 40 mg/kg/day for 4
consecutive days. Serum sickness prophylaxis with oral pred-
nisone 1 mg/kg/day was administered before the first dose of
ATG, continued for 10 days, and then tapered over the
subsequent week. CsA was administered from the time of h-
ATG initiation at 12 mg/kg/day by mouth (15 mg/kg/day for
children under age 12 years) in divided doses every 12 hours
and was continued for 6 months, with the dosage adjusted to
maintain blood levels between 200 and 400 ng/ mL. Serum
sickness prophylaxis, the 4-day h-ATG infusion, and the 6-
month CsA administration was the same for all 3 regimens
9,10
studied and has been described in more detail pre-viously.
CsA was discontinued after 6 months in all but 12 patients
who had the CsA tapered over 18 months (25% dosage
reduction every 3 months) after standard h-ATG/ CsA. MMF
2
was dosed on the first day of ATG at 600 mg/m twice daily
in children age 11 years and younger and at 1 g twice daily in
children age 12 and older and adults, for a total of 18 months.
Sirolimus was initiated on day 1 at 2 mg/day; in children
weighing 40 kg, the sirolimus dose was 1 mg/m /day,
2
administered for 6 months to a trough of 5 to 15 ng/mL.
Granulocyte colony-stimulating factor was not ad-ministered
routinely in conjunction with the IST. Patients underwent
bone marrow biopsy at 3, 6, and 12 months, and then yearly
thereafter. Evolution to myelodysplasia was de-fined as the
appearance of a new clonal disorder on cytoge-netics or
characteristic dysplastic changes on bone marrow.
Statistical Methods
Summary statistics, including means, proportions, and
their corresponding standard deviations were used to describe
patients’ age, sex, and other baseline characteristics. P values
based on multisample tests for proportions and analysis of
variance F-tests were used to compare patients’ baseline char-
acteristics across the treatment groups. Sample proportions and
their 95% confidence intervals (CIs) were used to describe the 6-
month response rates for patients categorized by dis-crete risk
factors. Multisample tests for proportions were used to compare
the 6-month response rates for patients in differ-ent risk groups.
Long-term survival probabilities for patients with discrete and
continuous baseline risks were evaluated using Kaplan-Meier
estimates and the Cox proportional haz-ard models, with
patients who were lost to follow-up counted as censored. The
numerical results were computed using the
Table 1. Patient characteristics
h-ATG/CsA h-ATG/CsA/MMF h-ATG/CsA/Rapa
All patients (1989 to 2006) (2000 to 2003) (2003 to 2005) P
n (%) Mean SD n (%) Mean SD n (%) Mean SD n (%) Mean SD value
Total 77 — 46 — 21 — 10 —
Age, years 11.4 0.52 11.6 0.66 11 1.1 11.8 1.5 .85
Sex
Male 50 (65) — 29 (63) — 14 (67) — 7 (70) —
.90
Female 27 (35) — 17 (37) — 7 (33) — 3 (30) —
Etiology
Idiopathic 69 (90) — 41 (89) — 18 (86) — 10 (100) —
.48
Posthepatitis 8 (10) — 5 (11) — 3 (14) — 0 —
Baseline ANC (/mL) 289 31 290 44 268 47 335 81 .83
Baseline ALC (/mL) 1264 78 1295 103 1162 149 1335 216 .72
Baseline ARC (/mL) 20 540 2244 19 232 3013 23 021 4185 21 344 5873 .76
Baseline platelets (/mL) 11 390 1158 10 283 1264 14 619 3062 9700 1832 .23
PNH
1% 28 (74) — 7 (64) — 13 (72) — 8 (89) —
.46
$1% 10 (26) — 4 (36) — 5 (28) — 1 (11) —
h-ATG/CsA/Rapa, h-ATG CsA sirolimus; PNH, paroxysmal nocturnal hemoglobinuria; SD, standard deviation.
Results of the Ham test before 2000 are not shown; only the detection of a PNH clone by flow cytometry, as described in the Methods section, is shown.

S-PLUS statistical package (Insightful Inc, Seattle, Washing-

ton).

RESULTS
A total of 84 children (under age 18 years) were treated
with initial IST between 1989 and 2006 at the National
Institutes of Health Clinical Center. Only patients initially
treated with an h-ATG– based immunosuppressive regimen
were included in the present analysis; any patients who re-
ceived alternative initial investigational treatments (cyclo-
phosphamide, rabbit ATG, or alemtuzumab) were excluded.
Thus, a total of 77 children were analyzed for response,
relapse, clonal evolution, and survival. Our cohort’s baseline
characteristics are summarized in the Table, and its age dis-
tribution is shown in Figure 1 (available at www.jpeds. com).
There were no significant differences in baseline char- Figure 2. Cumulative incidence of relapse (with 95% CIs) among
acteristics among the 3 treatment groups. pediatric patients after successful initial treatment with h-ATG– based
IST.

Response to h-ATG–Based IST and Relapse in
Children under Age 18 Years
The overall response rate in children at 6 months was
74% (57/77); 35% had a CR and 65% had a PR. All of the
children achieved transfusion independence. The cumulative
incidence of relapse at 10 years was 33%: the median time to
relapse was 558 days (Figure 2). No difference in the inci-
dence of relapse was seen between those with CR and those
with PR. Of the 14 patients who relapsed, 1 underwent a
matched sibling HSCT (alive) and 2 underwent an alternative
donor (AD) HSCT (1 of whom died), 6 were retreated with
CsA or a repeat course of IST (all of whom are alive), 2 were
lost to follow-up, and 3 died from infectious complications.
In total, 4 patients who relapsed after initial IST died. Among
the 16 patients who were nonresponders at 6 months, 6
underwent an AD HSCT (3 of whom died and 3 of whom are
alive), 3 underwent a matched sibling donor HSCT and are
alive, and 5 received a repeat course of IST; of these latter 5
patients, 3 responded; 1 continues to receive supportive care,
and 1 died of a fungal infection.
The response rate was 80% (31/39) in the children
under age 12 years (the median age of the cohort) and 68%
(26/38) in those over age 12. In total, 37 patients had a
baseline ANC 200/mL, of whom 24 (65%) responded to IST,
and 40 patients had a baseline ANC $ 200/mL, of whom 33
(83%) responded to IST (P .12). When the 4 patients with an
ANC 200/mL who died before com-pleting 6 months of IST
were excluded, the response rate for the patients with
baseline ANC 200/mL rose to 73% (24/33).

816 Scheinberg et al The Journal of Pediatrics • December 2015


Figure 3. Cumulative incidence of evolution (with 95% CIs) after IST
with an h-ATG– based regimen.
Clonal Evolution and Survival in Children under Age
18 Years
The cumulative incidence of evolution to myelodyspla-
sia after IST was 8.5%; all 3 events occurred in the partial
responders (Figure 3). Cytogenetic abnormalities detected
after IST were monosomy 7 in 2 patients and deletion 13q in
1 patient. Of these 3 patients, 1 is alive after a matched-
sibling HSCT, 1 died after an AD HSCT, and 1 died of
complications from marrow failure. There were no cases of
evolution to leukemia.
Overall, 13 patients died (17%), with 4 occurring
within the 3 months after IST in patients with a pretreat-ment
ANC 100/mL (2 due to fungal infections, 1 due to bacterial
septicemia, and 1 due to gastrointestinal bleeding at a time
when blood products were not available for the patient) and
the other 9 occurring more than 6 months from first IST. The
latter group included 4 nonresponders (3 who died after an
AD HSCT and 1 who died of a fungal infection), 4 relapsed
patients (2 who died of a fungal infection, 1 who died after
an AD HSCT, and 1 who died of sepsis); and 1 patient who
died after an AD HSCT performed after evolution to
monosomy 7. The median time to death was 570 days. In
total, 13 patients underwent HSCT, including 4 from a
matched sibling donor (all 4 of whom are alive) and 9 from
an AD (of whom 4 are alive). Three of these 9 AD HSCTs
were performed in the early 1990s (all 3 of whom died), 1
was performed in the late 1990s (still alive), and 5 were
performed after 2000 (of whom 2 died).
The overall 10-year survival for the entire cohort was
80% (Figure 4A). When patients who underwent HSCT were
censored at time of transplantation, overall survival for the
cohort rose to 90% (Figure 4B). Long-term survival in the
patients who responded to IST was 89% (Figure 4C), and
survival for patients who completed 6 months of IST regard-
less of response status was 83% (Figure 4D).
Outcome of Patients Age 18 to 21 Years Treated with
h-ATG–Based IST
Because several children’s hospitals in the US treat
patients up to age 21 years, we conducted a separate analysis
Long-Term Outcome of Pediatric Patients with Severe Aplastic Anemia Treated with Antithymocyte Globulin and Cyclosporine817
in the 18- to 21-year age group. A total of 35 patients in this
age group were treated with h-ATG– based IST between
1989 and 2006; the overall hematologic response rate was
60% (21/35). Of the 21 responders, 7 (33%) relapsed. Two
patients evolved to monosomy 7, and 1 patient developed a
morphological diagnosis of myelodysplasia. Among the 14
nonresponders, 4 underwent HLA-matched sibling HSCT (all
of whom are alive), 1 underwent a haploidentical HSCT (and
died), 6 received a second course of IST with rabbit ATG (4
of whom responded), 2 died, and 1 is alive on supportive
care. Overall, 6 deaths occurred in this age group: 4 in
nonresponders, 1 in a patient who relapsed, and 1 patient
with a baseline ANC of 0/mL who died before completing 3
months of IST. The response rate in this age group approx-
imates that in adult SAA patients treated with IST.
DISCUSSION
HSCT often is the initial treatment in children with
SAA who have an HLA-matched sibling donor. This choice
is based on the findings of early retrospective studies demon-
strating the superiority of transplantation over IST in chil-
12-14
dren. In the 1990s, as better supportive care became
available, a similar retrospective study found comparable sur-
vival in children who underwent HSCT and those who re-
15
ceived IST. But those studies involved mainly patients
treated in the 1970s and 1980s with ATG monotherapy and
did not encompass the current intensive regimen of ATG
CsA, which has now been studied in 2 large prospective
studies in children. A German multicenter study of 114
children treated with ATG CsA found response rates of 61%
at 6 months and 74% at 12 months, with a 4-year survival
16
rate of 87%. A Japanese multicenter study of ATG CsA in
119 children with SAA found a hematologic response rate of
68% and a 3-year survival rate of 88%.
17
Our findings from the current retrospective analysis are
similar to these published studies. The response rate of 74%
after IST in children is superior to our previously reported rate
8
of approximately 60% in patients of all ages. The children who
responded to IST had a long-term survival rate of about 90%.
Several of the nonresponders to IST in our cohort underwent
matched-sibling or AD HSCT, with the better outcome seen in
the former group. More recently, AD HSCT has been performed
in patients who lack a genoidentical sibling; some centers have
reported outcomes rivaling those for matched-sibling HSCT.
18
However, data from large ret-rospective studies in Europe and
Japan suggest that the out-come for unrelated-donor HSCT
remains less favorable than that for matched-related HSCT due
to a higher incidence of
graft-versus-host disease, with a long-term survival of about
19,20
50%. In general, the outcome after HSCT (both related
donor and AD) is more favorable in children and in proce-
21-23
dures performed within the past 10 years. Despite ad-
vances in AD HSCT, prospective studies to date have been
small, optimal conditioning remains undefined, and follow-
24
up has been relatively short. Therefore, in view of the high
response and survival rate in children treated with IST, we
Figure 4. Overall survival (with 95% CIs) for the entire cohort, including A, those who underwent HSCT, B, of patients who underwent HSCT censored at
the time of transplant, C, of patients who responded to IST and D, of patients who completed 6 months of IST regardless of response status.
recommend that IST be offered as initial treatment in all
children with SAA who lack a matched sibling donor.
Although some methods for predicting the response to
IST have been suggested, to date none has been widely
accepted, due to lack of practicality or standardization. A
recently completed analysis of more than 300 patients of all
ages treated at our institution between 1989 and 2005 re-
vealed that 3 factors were predictive of response to IST at 6
months: (1) younger age, (2) higher pretreatment ARC, and
(3) and higher pretreatment absolute lymphocyte count
(ALC). In this analysis, patients with baseline ARC $ 25
000/mL and ALC $ 1000/mL had about an 80% response
rate, compared with a rate of only about 40% in those with
baseline ARC 25 000/mL and ALC 1000/mL. In general, the
baseline ARC had a more significant effect than the baseline
ALC. A similar analysis performed in our pedi-atric cohort
(age 18 years) found that baseline ALC was not predictive of
response to IST, but baseline ARC remained highly
predictive. In this 77-patient pediatric cohort, the re-sponse
rate was 65% (31/48) in those with a baseline ARC 25
000/mL and 90% (26/29) in those with a baseline ARC $ 25
000/mL (P .02). In a large European study, a low
818 Scheinberg et al
pretreatment ANC was found to be predictive of response to
25
IST in children. But we found no such association in our
study, possibly due to the smaller size of our cohort and the
early deaths occurring in patients with a pretreatment ANC
200/mL.
In summary, we report in this retrospective analysis
that 3 out of 4 children with SAA will respond to ATG CsA;
that overall long term survival is 80% and among responders
survival is 90%. Until the role of unrelated donor HSCT is
better defined, IST should be the treatment of choice among
pediatric patients who lack a matched sibling donor.
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Long-Term Outcome of Pediatric Patients with Severe Aplastic Anemia Treated with Antithymocyte Globulin and Cyclosporine819
Figure 1. Age distribution (with 95% CIs) of the pediatric patients with
SAA treated with h-ATG– based IST.

819.e1 Scheinberg et al The Journal of Pediatrics • December 2015