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Blood, Vol. 91 No. 10 (May 15), 1998:
pp. 3637-3645
Long-Term Outcome After Marrow Transplantation for Severe Aplastic
Anemia
By
H. Joachim Deeg,
Wendy Leisenring,
Rainer Storb,
Janet Nims,
Mary E.D. Flowers,
Robert P. Witherspoon,
Jean Sanders, and
Keith M. Sullivan
From the Fred Hutchinson Cancer Research Center and the University of
Washington School of Medicine, Seattle, WA.
 |
ABSTRACT |
We reviewed the records and reevaluated 212 patients with aplastic
anemia transplanted at the Fred Hutchinson Cancer Research Center
(FHCRC) between 1970 and 1993 who survived  2 years and who have been
followed for up to 26 years. Parameters analyzed included hematopoietic
function, chronic graft-versus-host disease (GVHD), skin disease,
cataracts, lung disease, skeletal problems, posttransplant malignancy,
depression, pregnancy/fatherhood, and the return to work or school, as
well as patient self-assessment of physical and psychosocial health,
social interactions, memory and concentration, and overall severity of
symptoms. Survival probabilities at 20 years were 89% for patients
without (n = 125) and 69% for patients with chronic GVHD (n = 86)
(the status was uncertain in 1 surviving patient). All patients had
normal hematopoietic parameters. Skin problems occurred in 14%,
cataracts in 12%, lung disease in 24%, and bone and joint problems in
18% of patients. Eleven patients (12%) developed a solid tumor
malignancy and 19% of patients experienced depression. Chronic GVHD
was the dominant risk factor for late complications. Seventeen patients
died at 2.5 to 20.4 years posttransplant; 13 of these had chronic GVHD and related complications. At 2 years, 83% of patients had returned to
school or work; the proportion increased to 90% by 20 years. At least
half of the patients preserved or regained the ability to become
pregnant or father children. Patients rated their quality of life as
excellent and symptoms as minimal or mild. In conclusion, marrow
transplantation in patients with aplastic anemia established long-term
normal hematopoiesis. No new hematologic disorders occurred. The major
cause of morbidity and mortality was chronic GVHD. However, the
majority of patients who survived beyond 2 years returned to a fully
functional life.
| |
INTRODUCTION |
WITH THE CHARACTERIZATION in the 1960s of
the human major histocompatibility complex (MHC) antigens, termed HLA,
marrow transplantation from an HLA-matched donor became a realistic
treatment option.1-3 Patients with severe aplastic anemia
were thought to present an ideal indication for transplantation:
hematopoietic stem cells from a normal donor would replace the
nonfunctioning marrow. Failure of sustained engraftment was a major
complication in early trials,4,5 but has been infrequent in
recent studies.6-8 Improved prophylaxis of
graft-versus-host disease (GVHD)9,10 has resulted in
survival of 90% of patients transplanted from an HLA-matched related
donor.11 As more patients have been observed for extended
periods of time after transplantation, some delayed complications have
been recognized,12,13 but only few studies have analyzed
long-term results.14-16 We have established a comprehensive
program to offer long-term service to transplant recipients and to
conduct investigations into delayed effects after marrow or
hematopoietic stem cell transplantation. The present analysis assessed
long-term outcome in patients with aplastic anemia who had survived a
minimum of 2 years posttransplant and who have been followed for up to
26 years.
| |
MATERIALS AND METHODS |
Patients.
Between 1970 and 1993, 370 patients with aplastic anemia received a
first marrow transplant at the Fred Hutchinson Cancer Research Center
(FHCRC).3,6,10,11,17,18 The present analysis focused on the
212 patients who survived for at least 2 years and who did not
experience graft rejection or receive a second transplant. Demographic
data are summarized in Table 1: 187 patients (88%) received a transplant from an HLA-identical sibling
donor, 17 (8%) from an HLA-nonidentical related donor, 3 (1%) from a monozygotic twin, and 5 (2%) from an unrelated volunteer donor.
Conditioning regimen and posttransplant care.
Conditioning regimens consisted of cyclophosphamide, antithymocyte
globulin (ATG), and total body irradiation (TBI) administered alone or
in combination. In addition to donor marrow, 66 patients also received
infusions of viable donor buffy coat cells as an antirejection measure
(Table 1). Among 209 patients transplanted from an allogeneic donor, 86 received GVHD prophylaxis with methotrexate (MTX) plus cyclosporine
(CSP), 111 with MTX, 7 with CSP, and 5 with other
combinations.3,10,19 Fifty-five patients (26%) developed
acute GVHD grades II-IV20 and were treated as
described.21 Eighty-six patients developed chronic GVHD and
received glucocorticoids, CSP, and less frequently other agents for
therapy.22 Other posttransplant supportive care has been
described.3,10,11,17-22
Long-term follow-up.
All patients underwent a "departure work-up" 3 months after
transplantation21 and all patients returned to the FHCRC at 1 year (and sporadically thereafter) for a "complete"
evaluation.23 Follow-up consisted initially of 6-monthly
and later of annual contacts with the physician's office and mailing
of a questionnaire to the physician to obtain objective data. If no
response was received within 2 months, a second letter was mailed.
Patients were contacted once yearly on their transplant anniversary,
and, beginning in August 1990, were mailed questionnaires. Last contact
with more than 96% of patients was within the past 5 years. Among the
6 patients without contact for 5 years, the minimum follow-up (at last
contact) was 9 years. The patients' responses supplemented results
obtained from the physicians and provided a self-assessment of
performance and well-being using visual analog scales.24
Considered under complications were (1) skin disease that was
cosmetically disturbing (scleroderma) or required physical therapy (contractures); (2) cataracts diagnosed incidentally or because of
visual impairment; (3) lung disease (chronic obstructive or restrictive
disease) as indicated by impaired performance or by pulmonary function
tests at a level less than 80% of predicted; (4) musculoskeletal
problems causing pain or requiring therapy (osteoporosis; avascular
necrosis with or without joint replacement); (5) depression (requiring
therapy; suicidal attempts; suicide); (6) malignancy (invasive or in
situ) developing after transplantation. We also ascertained whether
female patients had become pregnant or whether male patients had
fathered children.25
Statistical analysis.
Demographic data are reported using range and median values for
continuous variables. Survival curves were estimated using the
Kaplan-Meier method, censoring at the time of last contact. The time
scale on the survival figures begins at 2 years posttransplant, as
patients had to survive that long to be included in the study. Late
complications were estimated with cumulative incidence curves, treating
death before the event of interest as a competing risk and censoring at
the time of last contact.26,27 The probabilities of
continuing chronic GVHD or death with chronic GVHD were calculated using cumulative incidence methods. The impact of various factors on
late complications and survival was determined by univariable and
multivariable Cox regression analyses. Time to each of the following
endpoints was used: chronic GVHD, skin disease, cataracts, lung
disease, skeletal complications, depression, and pregnancy (or fathered
pregnancy). Time was censored at the date of last contact (or death for
nonsurvival models). For complications occurring more than once, time
to first occurrence was used. For analysis of pregnancy, patients were
considered at risk only at age 16 years at the time of analysis (but
might have been preadolescent at the time of transplantation).
Prognostic variables examined for their impact on late complications
included age at transplant, gender, prior acute GVHD, chronic GVHD, use
of ATG in the conditioning regimen, buffy coat, CSP alone or in
combination with other agents, and year of transplant. For
multivariable analysis, final models were determined based on step-down
regression methods (using P < .10 as inclusion criterion)
where year of transplant was forced into all models to account for
potential changes over time.
In addition to the objective data, yearly questionnaires addressed
self-perceived physical and psychological health, social interactions,
memory and concentration, overall severity of symptoms (on visual
analog scales), and whether patients had returned to work or school.
For each patient, we selected the questionnaire returned closest to the
midpoint of each time interval studied and compared responses between
groups with and without chronic GVHD and between children (<18 years)
and adults for each time interval. Comparisons were made using a
Wilcoxon's rank sum test or a  2 test. Time intervals
(midpoints) posttransplant were: 1 to 3 (2), 3 to 7 (5), 8 to 12 (10),
13 to 17 (15), and 18 to 22 (20) years. Because questionnaires were
sent beginning only in 1990, each interval contained patients
transplanted within different periods of time; it was not possible to
separate the impact of time since transplant from that of transplant
year.
| |
RESULTS |
Survival.
Patients have been followed for 2 to 26 years (median, 12 years)
posttransplant and are currently 7 to 58 years old (median, 32 years
old). Actuarial 20-year survival among patients without chronic GVHD (n = 125) was 89%, compared with 69% in patients with chronic GVHD (n = 86) (in 1 surviving patient, the GVHD status was uncertain). All 3 syngeneic recipients, 15 of 17 patients receiving HLA-nonidentical
related transplants, and all 5 patients receiving unrelated transplants
are currently surviving. All patients have normal hematologic
parameters.
For patients without chronic GVHD, the minimum, mean, and maximum
Karnofsky scores were 30 (a patient with recent surgery), 97, and 100, respectively (75th percentile, 100), compared with 60, 95, and 100 (75th percentile, 90) in patients with chronic GVHD (differences not
significant). Scores were comparable for patients receiving
HLA-identical or HLA-nonidentical or unrelated transplants, and no
significant impact of age (<18 and 18 years) was observed.
Similarly, no significant differences in Karnofsky scores were noted
between patients who were 2 to 5, 6 to 10, 11 to 15, 16 to 20 or more
than 20 years after transplant.
Delayed effects.
Among the 209 allogeneic recipients, 86 (41%) had chronic GVHD. Risk
factors are summarized in Table 2. The
incidence was higher after prior acute GVHD, but resolution of chronic
GVHD occurred over a similar time period. Five years after chronic GVHD
onset, 4% of patients had died with the disease, 64% had recovered, and 32% were on treatment. At 10 years, 8% of patients had
died and 10% were still requiring therapy
(Fig 1). The effect of chronic GVHD on
survival among patients transplanted from an HLA-identical related
donor is shown in Fig 2. Among patients without chronic GVHD (Fig 2A), the probabilities of survival were comparable for cohorts transplanted in 1970 to 1977 (87%), 1978 to
1984 (100%), and 1985 to 1992 (100%) (P = .29). Among
patients with chronic GVHD, the probabilities of survival for the same time intervals were 72%, 78%, and 100%, respectively (Fig 2B). In
univariable analysis, prior acute GVHD (P < .001), viable
donor buffy coat infusion posttransplant (P < .001), and
patient age (P = .001) significantly increased the risk of
chronic GVHD; there was a suggestion that ATG administered as part of
the conditioning regimen had a protective effect (P = .09). In
multivariable analysis, acute GVHD (P < .001) and donor buffy
coat infusion (P < .001) were significant risk factors; year
of transplant had a marginally significant effect (lower incidence in
recent years; P = .07) on the development of chronic GVHD.
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| Fig 1.
Chronic GVHD. Probability of continuing chronic GVHD and
death with GVHD over time after onset of chronic GVHD.
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| Fig 2.
Survival by year of transplant (1970 to 1977; 1978 to
1984; 1985 to 1992) in patients transplanted from a matched related donor. (A) In patients with chronic GVHD. (B) In patients without chronic GVHD.
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Analyses of factors affecting other late events are shown in
Table 3. Chronic GVHD and risk
factors for chronic GVHD also had an impact on other late
complications. Univariable analysis suggested that the use of CSP (GVHD
prophylaxis) and ATG (conditioning regimen) were associated with a
higher probability of posttransplant pregnancy than patients not
exposed to those agents; only year of transplant was significant in
multivariable analysis (higher probability in recent years; P = .002).
The cumulative incidences of several endpoints are shown in
Fig 3A through F. For this analysis,
patients were divided into four groups: (1) no acute, no chronic GVHD
(A C; n = 110); (2) acute, but no
chronic GVHD (A+C; n = 15); (3) no
acute, but chronic GVHD (AC+; n = 47);
and (4) both acute and chronic GVHD (A+C+; n = 39). Chronic skin problems, including scleroderma and contractures (Fig
3A) occurred in 14% of patients ranging from 0% to 2% in patients
without to 30% to 33% in patients with chronic GVHD (with or without
preceding acute GVHD). Cataracts (Fig 3B) developed in 12% of
patients, ranging from 3% in patients without acute and chronic GVHD
to 27% in patients with both acute and chronic GVHD. As shown
previously, in patients not exposed to TBI, cataracts occurred
exclusively in patients receiving steroids for the treatment of
GVHD.28,29 Restrictive or obstructive pulmonary disease (Fig 3C) developed in 24% of patients, ranging from 13% in patients who never had GVHD to 45% in patients with de novo chronic GVHD, ie,
in patients who had not received immunosuppressive treatment other than
GVHD prophylaxis early posttransplant. The case fatality rate was 17%.
One additional patient is surviving 2 years after a lung transplant.
Aseptic necrosis (requiring joint replacement in 11 patients) or severe
osteoporosis (Fig 3D) occurred in 18% of patients, ranging from 0.1%
in patients with acute, but no chronic GVHD, to 22% in patients with
both acute and chronic GVHD. Eleven posttransplant solid tumor
malignancies were observed (12%) (Fig 3E). The probability was highest
(30% at 20 years) in patients with both acute and chronic GVHD and
lowest (0%) in patients with prior acute, but without chronic GVHD.
Ten neoplasms were squamous cell carcinomas of skin or mucous membranes
and one was an adenocarcinoma of the cervix.30 As reported
previously,31 carcinomas of the oropharyngeal mucosa
occurred exclusively in patients with chronic GVHD. Carcinomas of the
skin were seen in patients with or without GVHD. Three patients died of
progressive disease and eight are surviving after surgery. Nineteen
percent of patients experienced depression requiring therapy, or
attempted suicide (one successful) (Fig 3F), with a probability ranging
from 0% in patients with acute, but no chronic GVHD, to 38% in
patients with both acute and chronic GVHD.
Pregnancy.
At 20 years posttransplant, the probability that a female patient would
become pregnant was 47% (ranging from 26% in patients with acute and
chronic GVHD to 61% in patients with de novo chronic GVHD) and the
probability that a male patient had fathered a child was 50% (ranging
from 29% in those with acute and chronic GVHD to 62% among patients
with neither acute nor chronic GVHD). It was not possible to determine
precisely what proportion of patients had attempted to have children.
These results have been reported in detail previously.25
School and employment.
At 2 years, 83% of patients had returned to school or work; by 5 to 20 years, this proportion had increased to 86% to 90%. Among patients
less than 18 years old at transplant, 95% and 91% without and with
chronic GVHD had returned to school/employment, compared with 86% and
77%, respectively, for patients 18 years or older. None of these
differences were statistically significant.
Causes of death.
Among patients without chronic GVHD, 4 died of miscellaneous causes
(Table 4). Among patients with chronic
GVHD, 13 have died (Table 4). Among those transplanted in 1970 to 1977 (n = 16) no late deaths occurred until 13 years after transplantation; subsequent deaths were related to squamous cell carcinoma (n = 2),
human immunodeficiency virus (HIV) (n = 1), and pulmonary failure (n = 1). In patients transplanted in 1978 to 1984 (n = 39), deaths occurred
earlier and were generally related to pulmonary failure and infection
(n = 8). In the cohort transplanted in 1985 to 1992 (n = 31),
1 patient died of pulmonary failure.
Patient self-assessment.
Beginning in 1990, patients were also mailed questionnaires requesting
self-assessment. These questionnaires were sent to all surviving
patients regardless of the posttransplant interval. At least one
questionnaire was completed by 164 patients, and 77 patients completed
two. Compliance was highest for patients transplanted in early years
and decreased among patients transplanted more recently
(Table 5). As shown in Table
5, compliance was not different in patients with and patients without
chronic GVHD.
Results of self-assessment of physical, social and mental health, and
severity of symptoms are summarized in Table 5. Among these 2-year
survivors, no significant differences over time posttransplant were
observed for any individual parameter. There was a suggestion that
chronic GVHD had a significant effect (P = .07 at 10 years) and that age 18 years increased the severity of symptoms (P < .001) at the 5-year point, but not subsequently. In other words, patients who had survived at least 2 years posttransplant remained rather stable over more than 2 decades of follow-up.
| |
DISCUSSION |
To provide a long-term perspective of treatment results, we evaluated
the outcome in patients with aplastic anemia transplanted at the FHCRC
and surviving 2 years posttransplant. With follow-up reaching to 26 years, these patients have an excellent life expectancy and most are
doing well. Chronic GVHD, which had developed in 41% of patients, was
the most frequent late event31,32 and had an impact on
survival: 89% of patients without chronic GVHD were projected to
survive at 20 years, compared with 69% for those with chronic GVHD.
Thirteen of 17 patients who died at 2.5 to 20.4 years had chronic GVHD;
none of the four late deaths in patients without chronic GVHD was
directly transplant-related. Risk factors for chronic GVHD were those
recognized in earlier studies, ie, acute GVHD, infusion of viable donor
buffy coat cells, and older patient age.33 The omission of
buffy coat infusion has significantly reduced the incidence of chronic
GVHD.11 ATG as part of the conditioning regimen may be
associated with less chronic GVHD,11 an observation similar
to that in patients given Campath 1 antibody before transplantation
from an unrelated donor.34 Improved supportive care in
recent years appears to have increased survival by reducing mortality
in the first 2 years posttransplant.31 Interestingly, patients transplanted before 1978 who developed chronic GVHD and survived 2 years were as likely to survive as patients without chronic
GVHD, presumably because those with the most severe problems died
early, ie, before 2 years.
Chronic GVHD emerged as a risk factor for nearly all long-term
complications. Aside from a direct involvement of target
organs by GVHD (skin, lungs), treatment of GVHD, especially
with steroids, enhanced the likelihood of delayed
complications such as cataracts or musculoskeletal
disease.21,24,35 In fact, cataracts and aseptic necrosis
occurred exclusively in patients who had received glucocorticoids. On
the other hand, pulmonary problems were most frequent in patients with
de novo chronic GVHD. This observation suggests the possibility that
late institution of GVHD therapy in patients who never had clinically
apparent acute GVHD allowed for the development of pulmonary
pathology.32,36 Posttransplant malignancies developed in 11 patients, five with and six without chronic GVHD. In two patients, the
underlying diagnosis was Fanconi anemia. Although no significant
risk factor for the development of a posttransplant malignancy was
identified in the present analysis, in a recent study of 700 patients
with aplastic anemia, treatment of chronic GVHD with azathioprine
emerged as a significant risk factor.30
We have shown previously that patients with aplastic anemia conditioned
for transplantation with a nonirradiation regimen were likely to
preserve their ability to become pregnant or father normal
children.25 This finding was confirmed in the present analysis, although it is unknown how many of the patients attempted to
have children. It is also not clear why transplantation in more recent
years was associated with a higher likelihood of posttransplant pregnancy.
We also attempted to evaluate the patients' current status by means of
self-assessment questionnaires.24 In agreement with at least one other report,35 neither time from
transplant nor the presence of chronic GVHD had a significant
impact on the patients' self-assessment score, although
there was a trend for patients with chronic GVHD and for older patients
to score lower than patients without GVHD and younger patients. A
negative effect of age on posttransplant assessment was observed by
Schmidt et al37 and by Baker et al38 and was
thought to be related to an increase in chronic GVHD incidence with
age. Regardless of GVHD, however, patients generally assessed their
quality of life as excellent. By 2 years posttransplant, 83% of
patients were employed or had returned to school; this proportion had
increased to 86% to 90% by 15 to 20 years. These numbers compare
favorably with the 55% to 65% employment reported for allogeneic
transplant recipients treated for various malignant
diseases39,40 and are similar to those in autologous
transplant recipients.41
The present analysis confirms that marrow transplantation offers
effective therapy for patients with aplastic anemia. Most patients who
survived for at least 2 years posttransplant returned to a productive
life. The likelihood was higher in patients without chronic GVHD. The
probability of being well and returning to a functionally satisfactory
lifestyle was somewhat better than reported for patients transplanted
for a malignant disorder.39,40 At last follow-up, all
patients had normal hematopoiesis derived from donor cells, providing
proof that small numbers of stem cells allow for long-term effective
hematopoiesis. In contrast to patients given immunosuppressive
therapy,42-45 none of the transplanted patients developed a
new hematologic disorder. While some posttransplant malignancies
developed, most were treated successfully; only three patients, all of
whom had chronic GVHD, died. A large proportion of both female and male
patients preserved (or gained) the ability to have children. The
overall self-assessment of patients indicated an excellent level of
satisfaction and reintegration into societal networks. Efforts must be
directed at the prevention and efficient therapy of chronic
GVHD.
| |
FOOTNOTES |
Submitted July 31, 1997;
accepted December 31, 1997.
Supported in part by Public Health Service Grants No.
HL36444, CA18221, CA15704, and by contract N01 CP51027 awarded by the National Institutes of Health, Department of Health and Human Services, Bethesda, MD. H.J.D. is also supported by a
grant from the National Marrow Donor Program (Minneapolis/St Paul,
MN).
Address reprint requests to H. Joachim Deeg, MD, Fred Hutchinson Cancer
Research Center, 1100 Fairview Avenue N, PO Box 19024, Seattle, WA
98109.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
| |
ACKNOWLEDGMENT |
The authors thank all patients and their physicians and nurses who have
continued to provide us with follow-up information for as long as 26 years. We appreciate the efforts of the staff in the Long-Term
Follow-Up Department, in particular Kathy Erne, Muriel Siadak, Judy
Campbell, Deborah Monroe, and Marianne Hansen. We thank Bonnie Larson
and Harriet Childs for typing the manuscript.
| |
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Abstract
Introduction
Abstract
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