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Blood, Vol. 92 No. 8 (October 15), 1998:
pp. 2742-2749
Decreased Rejection and Improved Survival of First and Second Marrow
Transplants for Severe Aplastic Anemia (A 26-Year Retrospective
Analysis)
By
Anne Stucki,
Wendy Leisenring,
Brenda M. Sandmaier,
Jean Sanders,
Claudio Anasetti, and
Rainer Storb
From the Clinical Research Division, Fred Hutchinson Cancer Research
Center, and the Departments of Medicine and Pediatrics, University of
Washington, Seattle, WA.
 |
ABSTRACT |
Between 1970 and 1996, 333 patients with severe aplastic anemia
underwent HLA-matched related marrow transplant after conditioning with
cyclophosphamide (CY). Thirty-five percent of patients transplanted between 1970 and 1976 (group 1), 12% of those transplanted between 1977 and 1981 (group 2), and 9% of patients transplanted between 1982 and 1997 (group 3) had graft rejection. Graft rejection occurred later
among group 3 patients (median, 180 days) than among those in groups 1 and 2 (medians, 28 and 47 days, respectively; P < .001 group
3 v 2). In group 3, 92% of rejecting patients underwent a
second transplant, compared with 78% and 77% in groups 1 and 2, respectively. Group 1 patients received various conditioning regimens
before second transplant, whereas most patients of groups 2 and 3 received CY combined with antithymocyte globulin (ATG). Graft-versus-host disease (GVHD) prophylaxis after second transplant consisted of methotrexate (MTX) for all group 1 and 2 patients, whereas
group 3 patients received MTX combined with cyclosporine (CSP). Over
the three time periods studied, first graft rejection decreased from
35% to 9%, and the proportion of rejecting patients undergoing second
transplants increased from 77% to 92%. The 10-year probability of
survival after second transplants increased from 5% to 83%.
Multivariate analysis showed MTX/CSP GVHD prophylaxis to be a
significant factor accounting for the increase in patient survival
after second transplant.
© 1998 by The American Society of Hematology.
| |
INTRODUCTION |
GIVEN THEIR NEAR NORMAL or normal T-cell
responsiveness,1,2 patients with severe aplastic anemia
(sAA) must be conditioned for allogeneic marrow transplants with
immunosuppression to control T-cell mediated host-versus-graft (HVG)
reactions and prevent graft rejection. Animal studies in the
1960s3-5 identified cyclophosphamide (CY) as a suitable
conditioning agent that combined efficient immunosupression with
acceptable toxicities when compared with total body irradiation (TBI).
Indeed, since the first report of successful marrow allografts in
patients with sAA in 1972,6 CY has remained the
conditioning regimen of choice at the Fred Hutchinson Cancer Research
Center (FHCRC; Seattle, WA) for those patients whose donors are
HLA-matched family members.
With CY conditioning, sustained engraftment occurred in 90% of
patients, and survival was 75%7 when patients were
untransfused at the time of transplant. However, most patients referred
for transplant were multiply transfused, and marrow graft rejection was
seen in 30% to 70% of patients transplanted in the
1970s.8-13 Factors associated with rejection were
transfusions before transplant (resulting in sensitization to minor
histocompatibility antigens) and low marrow cell dose (<3 × 108/kg of body weight).14 The avoidance of
transfusions, the use of  -irradiated leukocyte depleted blood
products, and the infusion of larger numbers of donor hematopoietic
stem cells derived from marrow supplemented by peripheral blood buffy
coat cells9,15 decreased rejection and improved survival,
although the buffy coat cells increased the incidence of chronic
graft-versus-host disease (GVHD). Also over time, more efficient
immunosuppressive conditioning regimens were introduced such as the
combinations of CY with antithymocyte globulin (ATG) or with total or
partial body irradiation.16-19
Finally, improved postgrafting immunosuppression with the combination
of methotrexate/cyclosporine (MTX/CSP) compared with monotherapy for
GVHD prevention may also have decreased the rejection rate by
suppressing HVG reactions, as shown in animal studies.20 Owing to the changes in transfusion support and transplant techniques, the risk of rejection of first transplants in sAA patients has declined. Furthermore, for those patients undergoing a second transplant, the case fatality rate has decreased dramatically over the
last three decades.
This report describes the changing incidence of graft rejection among
333 patients with sAA who received HLA-identical related marrow grafts
at FHCRC since 1970 and analyzes the factors involved in increased
survival after second transplants.
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MATERIALS AND METHODS |
From 1970 to 1996, 333 patients with sAA received HLA-identical related
marrow transplants at the FHCRC after conditioning with CY. Patient
data are shown in Table 1 for first
transplants and Table 2 for second
transplants. The patients were a median of 20.4 years old (range, 1.8 to 60.3 years old) at the time of first transplant and were 0.3 to 228 months (mean, 7.9 months; median, 1.9 months) from diagnosis. Diagnoses
established at the referring institution were confirmed at this
institution by review of outside marrow specimens and repeat marrow
aspirates and biopsies. All patients had normal marrow cytogenetic
findings. Marrow donors were HLA-A, HLA-B, and HLA-DR identical
relatives. Mixed leukocyte culture was performed in all patients before
the introduction of HLA-DR typing. One second graft was performed using
peripheral blood stem cells (PBSCs); for all other grafts, the source
of stem cells was marrow.
For purposes of the analysis, patients were divided into three groups
reflecting time periods that coincided with changes in preparative
regimens and GVHD prophylaxis used for first and second transplants.
Accordingly, 81 patients transplanted from 1970 to 1976 constituted
group 1, 104 patients transplanted from 1977 to 1981 were included in
group 2, and group 3 consisted of 148 patients transplanted from 1982 to 1996.
Patients were referred to FHCRC after detailed consultation with their
physicians and treated after outpatient and inpatient conferences that
fully outlined the advantages and disadvantages of the transplant.
Treatment protocols and consent forms were approved by the
Institutional Review Board of the FHCRC.
First transplants.
Preparative regimen for first transplants included CY
alone6 at 50 mg/kg intravenously (IV) for 4 consecutive
days for 262 patients, CY plus procarbazine at 12.5 mg/kg IV on days
 9, 7, and 5, alternating with rabbit ATG at 12 mg/kg subcutaneously on days 8, 6, and 4 for 19 patients,21 CY plus IV horse ATG (ATGAM; Upjohn Co,
Kalamazoo, MI) at 30 mg/kg/dose, 12 hours after the first, second, and
third dose of CY for 52 patients.19
GVHD prophylaxis was MTX only at 15 mg/m2 on day 1 followed
by 10 mg/m2 on days 3, 6, and 11 and then once weekly until
day 102 for 196 patients.6,21 Sixteen patients received CSP
only at 1.5 mg/kg IV BID from day 1 through day 50, followed by
progressive taper until day 180,22 whereas 121 patients
received a short course of MTX (15 mg/m2 IV on day 1 and 10 mg/m2 on days 3, 6, and 11) combined with CSP in the dose
schedule outlined above.23
Donor buffy coat infusions were administered to 125 patients in
addition to the marrow as part of a prospective study.23
Assessment of hematopoietic engraftment and grading and treatment of
acute and chronic GVHD were performed as previously
described.24-26 Graft rejection was defined as either a
failure to reach a granulocyte count greater than 1,000/µL for at
least 3 consecutive days or by a progressive decrease in peripheral
blood counts after initial engraftment, along with the redevelopment of
an aplastic marrow. In addition, the disappearance of donor
hematopoietic cells and reappearance of T lymphocytes of host origin
were interpreted to represent graft rejection. In patients with
sex-mismatched grafts, cytogenetics and more recently fluorescence in
situ hybridization (FISH) analyses were used to monitor the graft. In
the past, polymorphism in white blood cell enzymes served to assess
grafts and graft rejection, whereas assays of DNA-based polymorphisms
have been used since the mid-1980s.
Second transplants.
A variety of second transplant regimens were administered to group 1 patients, which included TBI (Table 2). CY/ATG became the standard
regimen after 1977,27 except for 3 patients in group 3 who
were either conditioned with IV CY at 120 mg/kg, followed by 1,200 cGy
fractionated TBI (n = 2), or with 20 mg/kg/d methylprednisolone followed by taper through day 60 combined with IV anti-CD3 (BC3) monoclonal antibody at 0.4 mg/kg on day 1, 0.2 mg/kg on days 0 through 19, followed by progressive taper through day 26 (n = 1).28 Posttransplant GVHD prophylaxis consisted of
long-term MTX (until day 102) for all patients of groups 1 and 2, whereas all group 3 patients received MTX/CSP.
Statistics.
Survival curves were calculated using Kaplan-Meier
estimates.29 Incidence of graft rejection was calculated
using cumulative incidence estimates where death before rejection was
treated as a competing risk event.30 When survival or
rejection after second transplant was shown, the time scale began at
the time of second transplant. Comparisons of factors between patients
transplanted in different time periods were performed using
 2 tests (or Fisher's exact test, where appropriate),
Wilcoxon's rank sum test, or logrank test. Among patients receiving a
second transplant between 1977 and 1996, the impact of factors on
survival after the second transplant was evaluated using Cox
proportional hazards regression.30 Variables examined
included age at second transplant, gender, cell dose administered at
transplant, length of interval between first and second transplant,
date of second transplant (after 1982 v before 1982), and
whether patients received MTX/CSP as GVHD prophylaxis versus MTX alone.
Univariate models were initially examined. Because of the small number
of patients in this study, full multivariate models with all variables
could not be fit, although models including two variables at a time were evaluated.
| |
RESULTS |
Tables 1 and 2 present the patient characteristics and results of first
and second transplants for the three patient groups.
First transplants.
Median patient ages at first transplant gradually increased over the
three time periods (P = .04, group 3 v group 2). The time from diagnosis to transplant was the shortest between 1977 and
1981 (P < .0001, group 2 v group 1; P = .051, group 2 v group 3). Nearly all group 1 patients had multiple
preceding transfusions, whereas almost one third of group 2 patients
were untransfused (P = .26). In group 3, 78% of patients had
prior transfusions. The marrow cell doses infused were comparable
between the three groups, but all group 2 patients and approximately
one third of the group 1 and 3 patients received additional buffy coat
cell infusions from their donors.
Overall, 53 patients (16%) rejected their first marrow graft. The
highest rejection incidence (35%) was seen in group 1 patients, compared with 12% in group 2 (P < .001) and 9% in group 3 (P = .27, group 2 v group 3; Table 1 and
Figs 1 and 2).
Not only was rejection more frequent in earlier than in later patients,
but rejection occurred significantly earlier in patients of groups 1 and 2 than in those of group 3 (P < .001; Fig 2).
Specifically, the median time to rejection in group 1 patients was 28 days (range, 14 to 984 days), compared with 47 days (range, 14 to 215 days) in group 2 patients and 180 days (range, 22 to 583 days) in group 3 patients.
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| Fig 1.
Incidences of rejection of first marrow graft, second
grafts, and survival after second transplants among patients with
aplastic anemia. Results are shown for three time periods: 1970 to
1976, 1977 to 1981, and 1982 to 1996.
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| Fig 2.
Probabilities of and times to graft rejection among 333 patients with sAA who underwent a first marrow graft after CY. Results
are shown for three time periods: 1970 to 1976, 1977 to 1981, and 1982 to 1996.
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Second transplants.
The median patient ages at second transplant were comparable among
groups 1 and 2 patients (P = .75), whereas group 3 patients were younger (median age, 10.6 v 20.3 years; groups 3 v
group 2, P = .09).
In direct relation to the time to rejection, intertransplant intervals
were the shortest in group 1 (median, 37 days) and group 2 patients
(median, 57 days; P = .30, group 1 v 2) and the longest
in group 3 patients (median, 226 days; P < .001, group 3 v 2; Table 2 and Fig 2). The percentage of rejecting patients undergoing second transplants increased from about 77% (groups 1 and
2) to 92% (group 3; Fig 1). Those patients who did not receive second
transplants either died before they had completed their second
conditioning regimen (n = 3), showed autologous hematopoietic recovery
(n = 4) before or during the second conditioning regimen, had developed
secondary AML (n = 1), or, in yet another case, chose not to
return to FHCRC for the recommended second transplant. The latter
patient died of fungal infection several weeks after rejection was
diagnosed. Furthermore, owing in part to the temporal proximity to the
first transplant and in part to the greater intensity and toxicity of
the conditioning regimens used in the earlier patients, approximately
one third of group 1 patients died from toxicities or infections, too
early after the second transplant for engraftment to be evaluated
(Table 2). This percentage declined in the subsequent two time periods
to 0% and 8.4%, respectively.
One third of group 1 and half of the group 2 patients rejected their
second grafts. In group 1, all rejecting patients died from
complications related to the prolonged pancytopenia. In group 2, 3 of 5 rejecting patients died from infections (1 from cardiomyopathy), and 1 recovered normal host hematopoiesis and is alive more than 15 years
after second transplant. By comparison, only 3 patients of group 3 (25%) rejected the second graft, and all 3 are surviving with
successful third grafts. Sustained second engraftment increased from
36% among group 1 patients to 50% and 67% in patients of groups 2 and 3, respectively (P = .04, group 3 v group 1;
P = .68, group 2 v group 1).
Overall, only 1 of 6 engrafting patients in group 1 is alive, whereas
the remainder died of infections between days 17 and 173. Similarly,
only 1 of the 5 successfully engrafted group 2 patients is surviving;
the remaining 4 patients died between 0.6 and 10 years, 3 from
infectious complications associated with chronic GVHD and 1 from
pulmonary hypertension. By comparison, all 8 engrafted patients in
group 3 are alive, with follow-ups ranging from 2.8 to 12.2 years.
Acute grade 2-4 GVHD occurred in 2 of 6 (33%) group 1 patients with
successful engraftment versus 5 of 5 (100%) group 2 patients (P = .06) and 2 of 8 (25%) group 3 patients (P = .02, group 2 v group 3). The use of MTX+CSP clearly
contributed to the improved survival in group 3 patients, as shown in
Table 3 and Fig
3. The incidence of chronic GVHD among patients with sustained
engraftment was 0% in group 1 patients, 80% in group 2 (P = .02, group 2 v group 1), and 50% in group 3 patients
(P = .57, group 2 v group 3).
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| Fig 3.
Probability of survival among 22 aplastic anemia patients
who were conditioned with CY/ATG for their second marrow graft and
received either MTX alone or the combination of MTX/CSP as postgrafting
GVHD prophylaxis.
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Figure 4 illustrates the improved survival
after second transplants over the three time periods. Survivals
increased from 5% (group 1) to 20% (group 2) and 83% (group 3),
respectively.
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| Fig 4.
Ten years probability of survival for 44 patients with
aplastic anemia receiving second marrow transplants between 1970 and
1976, 1977 and 1981, and 1982 and 1996.
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Analyses of factors influencing survival in patients conditioned for
second transplants with CY/ATG (groups 2 and 3).
Second transplant parameters included in the univariate analysis (Table
3A) showed that younger patient age (<18 years), longer intervals
between first and second transplants, use of MTX+CSP GVHD prophylaxis,
and not receiving buffy coat infusions were associated with improved
survival after second transplant. Multivariate analysis showed the only
significant factor to be MTX+CSP GVHD prophylaxis (Fig 3 and Table 3B).
| |
DISCUSSION |
Survivals of patients treated with marrow graft from HLA-identical
family members at FHCRC have increased from 41% in the first half of
the 1970s to 90% during the late 1980s and 1990s. At least three
factors have contributed to the improvement in transplant outcome. One
is the significant reduction in the incidence, severity, and mortality
from acute GVHD. This has been accomplished through improved GVHD
prophylaxis with the combination of MTX/CSP compared with either MTX or
to CSP alone.23,31 The second factor is a decreased
incidence of marrow graft rejection, from initially 35% to the current
9%. The third factor is increased survival after second transplants,
which has increased from 5% to 83%. Accordingly, the overall
mortality associated with graft rejection has decreased from 30% to
1.4 % over the 26-year study period. In fact, no patient has died due
to graft rejection since 1988.32
Graft rejection in patients transplanted for aplastic anemia is usually
the result of transfusion-induced sensitization to minor
histocompatibility antigens, as documented in prospective animal
studies33,34 and corroborated by analyses of results in
transfused patients compared with those who were untransfused at the
time of transplantation.7,35 Ninety-one percent of patients
in group 1 had multiple transfusions; consequently, the rejection
incidence was high. The progressive decrease in the rejection rates
over the past 26 years has several reasons. Firstly, the percentage of
untranfused patients increased from 9% in group 1 to 31% and 22% in
groups 2 and 3, respectively. Secondly, increasing numbers of
transfused patients received blood products from which antigen-presenting leukocytes have been removed (leukopoor) and which
have been irradiated in vitro before administration. Both manipulations
reduced the risk of graft rejection in animal studies.36-38 Thirdly, most transfused patients in group 2 and many of those in group
3 (through June 1988) received donor buffy coat cell infusions in
addition to the marrow graft, which were administered in an attempt at
increasing the number of transplanted stem cells.39 Buffy
coat cell infusions were discontinued in mid-1988 because of the
unusually high incidence of chronic GVHD seen with this treatment
modality.40 Fourthly, there have been improvements in the
immunosuppressive quality of conditioning programs. For example,
beginning in July 1988, all patients transplanted at FHCRC have been
conditioned for their first graft with a combination of
CY/ATG,19 which was known to be an effective conditioning program for second transplants.27 Other centers introduced
radiation in the conditioning regimens, either in the form of TBI or
partial body irradiation such as total lymphoid or
thoraco-abdominal41 irradiation. Although effective in
reducing rejection,17,42-44 the inclusion of irradiation
may have increased the risks of GVHD,18,42 interstitial
pneumonia,42,45 and secondary cancers, compared with
CY-based regimens.46 Also, growth, development, and
fertility may be impaired in irradiated patients.47-49 By
comparison, no unusual short- or long-term side effects have been
observed as yet with the CY/ATG regimen.32
Almost concurrent with the progressive decrease in rejection rates,
survivals after second transplants increased. One important factor
contributing to this success has been a significant delay in the time
to rejection of the first graft from a median of 28 days among group 1 patients to 180 days in group 3 patients. In direct relation to the
times to rejection, the intertransplant intervals increased. Patients
undergoing second transplants after a longer intertransplant interval
had recovered from toxicities associated with the first graft, and they
were in much better clinical condition than those transplanted sooner
after the first graft. Consequently, the patients were less likely to
die from toxicities related to the second transplant regimen. The
significantly delayed times to rejection in more recent patients are
likely the result of the use of the short course of MTX combined with CSP for at least 6 months after transplant, compared with the earlier
monotherapy with intermittent (once weekly) MTX for at most 3 months. Thus, although rejection rates in MTX/CSP treated patients were
not significantly lessened, rejections that were observed occurred
significantly later than in MTX-treated patients. In addition, MTX/CSP
administered after second transplant reduced the severity of
posttransplant related complications related to GVHD, thereby
increasing patient survival. Other factors may also have been
important, such as substituting the CY/ATG conditioning regimen for the
previously used TBI containing regimens. However, with the small
numbers of patients studied, the effect of the conditioning regimen was
not found to be significant. Finally, gradual improvements in the
quality of supportive care may also have contributed to the current
success with second transplants.
| |
FOOTNOTES |
Submitted March 3, 1998;
accepted June 11, 1998.
Supported by grants from the Swiss National Foundation for Scientific
Research, the Swiss League Against Cancer, the Fern Moffat Foundation
of the Academic Society of the State of Vaud, Switzerland, and Grants
No. HL36444 and CA15704 from the National Institutes of Health, DHHS
(Bethesda, MD).
Address correspondence to Rainer Storb, MD, Fred Hutchinson Cancer
Research Center, 1100 Fairview Ave N, D1-100, 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" is accordance with 18 U.S.C. section 1734 solely to indicate this fact.
| |
ACKNOWLEDGMENT |
The authors thank Harriet Childs and Bonnie Larson for their assistance
in manuscript preparation and Deborah Monroe and Gary Schoch for their
help in data collection.
| |
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Abstract
Introduction
Abstract