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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 94 No. 7 (October 1), 1999:
pp. 2208-2216
Risk of Lymphoproliferative Disorders After Bone Marrow
Transplantation: A Multi-Institutional Study
By
Rochelle E. Curtis,
Lois B. Travis,
Philip A. Rowlings,
Gérard Socié,
Douglas W. Kingma,
Peter M. Banks,
Elaine S. Jaffe,
George E. Sale,
Mary M. Horowitz,
Robert P. Witherspoon,
Donna
A. Shriner,
Daniel J. Weisdorf,
Hans-Jochem Kolb,
Keith M. Sullivan,
Kathleen A. Sobocinski,
Robert Peter Gale,
Robert N. Hoover,
Joseph
F. Fraumeni Jr, and
H. Joachim Deeg
From the Division of Cancer Epidemiology and Genetics, and the
Division of Cancer Biology and Diagnosis, Laboratory of Pathology,
National Cancer Institute, Bethesda, MD; International Bone Marrow
Transplant Registry, Medical College of Wisconsin, Milwaukee, WI; Fred
Hutchinson Cancer Research Center, Seattle, WA; Hôpital Saint
Louis, Hématologie-Greffe de Moelle, Paris, France; Carolinas
Medical Center, Charlotte, NC; University of Minnesota Medical School,
Minneapolis, MN; Universität München, Munich, Germany; and
Salick Health Care, Inc, Los Angeles, CA.
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ABSTRACT |
We evaluated 18,014 patients who underwent allogeneic bone marrow
transplantation (BMT) at 235 centers worldwide to examine the incidence
of and risk factors for posttransplant lymphoproliferative disorders
(PTLD). PTLD developed in 78 recipients, with 64 cases occurring less
than 1 year after transplantation. The cumulative incidence of PTLD was
1.0% ± 0.3% at 10 years. Incidence was highest 1 to 5 months
posttransplant (120 cases/10,000 patients/yr) followed by a steep
decline to less than 5/10,000/yr among  1-year survivors. In
multivariate analyses, risk of early-onset PTLD (<1 year) was strongly associated (P < .0001) with unrelated or human
leukocyte antigen (HLA) mismatched related donor (relative risk
[RR] = 4.1), T-cell depletion of donor marrow (RR = 12.7), and use of antithymocyte globulin (RR = 6.4) or anti-CD3
monoclonal antibody (RR = 43.2) for prophylaxis or treatment of acute
graft-versus-host disease (GVHD). There was a weaker association with
the occurrence of acute GVHD grades II to IV (RR = 1.9, P = .02) and with conditioning regimens that included radiation (RR = 2.9, P = .02). Methods of T-cell depletion that selectively
targeted T cells or T plus natural killer (NK) cells were associated
with markedly higher risks of PTLD than methods that removed both T and
B cells, such as the CAMPATH-1 monoclonal antibody or elutriation
(P = .009). The only risk factor identified for late-onset
PTLD was extensive chronic GVHD (RR = 4.0, P = .01). Rates
of PTLD among patients with 2 or 3 major risk factors were 8.0% ± 2.9% and 22% ± 17.9%, respectively. We conclude that factors
associated with altered immunity and T-cell regulatory mechanisms are
predictors of both early- and late-onset PTLD.
This is a US government work. There are no restrictions on its use.
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INTRODUCTION |
ALLOGENEIC BONE MARROW transplantation
(BMT), an effective treatment for leukemia and other disorders,
produces profound immune deficiency in the early period after
transplantation. Posttransplant lymphoproliferative disorders (PTLD)
are an uncommon, but frequently fatal, complication of this defective
immune function.1-3 PTLD typically develop in the first 6 months posttransplant as clinically aggressive lymphomas of donor
origin; most are related to Epstein-Barr virus (EBV).1,4,5
Previous studies indicate that patients at highest risk of PTLD are
those receiving unrelated donor or human leukocyte antigen (HLA)
mismatched related donor transplants, T-cell depletion, or
antithymocyte globulin. However, prior studies of PTLD generally
included small numbers of cases treated in a single institution, and
did not separately analyze lymphoproliferative disorders that occurred
beyond the first posttransplant year. We evaluated the
long-term incidence, risk factors, and outcome of lymphoproliferative
disorders in a cohort of more than 18,000 allogeneic BMT recipients.
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MATERIALS AND METHODS |
Patients.
The study included 18,014 patients receiving allogeneic BMT at 234 transplant centers reporting to the International Bone Marrow
Transplant Registry (IBMTR), Milwaukee, between 1964 and 1990, and at
the Fred Hutchinson Cancer Research Center, Seattle, between 1969 and
1992. Because of the potential difficulty in distinguishing PTLD from
recurrent non-Hodgkin's lymphoma (NHL), we did not consider 729 patients transplanted for NHL. Also excluded were 577 patients
transplanted for Fanconi anemia or a primary immunodeficiency disease
who are known to have an increased susceptibility to
cancer.6,7 Complete follow-up data through the study end date (December 31, 1991 and December 31, 1992 for the IBMTR and Seattle
patients, respectively) were obtained for 91% of transplant recipients.
Table 1 lists subject- and
transplant-related characteristics. Eighty-nine percent of patients
received a transplant for leukemia or severe aplastic anemia; 81% of
donors were HLA-identical siblings. Median age at transplant was 25 years (range, <1 to 72). Common conditioning regimens consisted of
total body irradiation (TBI) combined with cyclophosphamide (64%) or
other cytotoxic drugs (8%). Patients not given radiation typically
received cyclophosphamide and busulfan (15%). In 14% of transplants,
the graft was depleted of T cells, with the most frequent methods using
monoclonal antibodies targeting T cells or T plus natural killer (NK)
cells, CAMPATH-1 monoclonal antibodies, or elutriation. Most patients
received posttransplant immune suppression to prevent graft-versus-host disease (GVHD), usually with cyclosporine, methotrexate, and/or corticosteroids. Acute GVHD was typically treated with
corticosteroids, cyclosporine (usually continued from prophylaxis),
antithymocyte (or antilymphocyte) globulin, or combinations of these
drugs. Twenty-one patients from Seattle received an anti-CD3
monoclonal antibody (64.1) to treat acute GVHD.8 Data on
drugs used to treat chronic GVHD were incomplete, and thus not further
analyzed.
We identified 78 PTLD using well-established criteria9;
some of these cases were described previously.2-3,10-15
Fifty-three cases (68%) were confirmed by centralized histopathologic
examination of archived tissue or slides (D.K., E.J.), 18% by review
of clinical and pathology reports (P.B.), 9% by review of published
case details,11,12,14 and 5% (4 cases) were evaluated
using the transplant team report only. Sufficient tissue was available
for 36 PTLD to perform in situ hybridization to detect expression of
EBV-encoded RNA (EBER1) (methods described in Kingma et
al16). Clonality and immunoglobulin gene rearrangement
studies were not performed.
Statistical analyses.
For each transplant recipient, person-years at risk were compiled from
the date of transplant until one of the following events: death, last
known follow-up, diagnosis of new malignancy (including PTLD), or end
of study, whichever occurred first. The change in PTLD risk over
posttransplant intervals was initially evaluated by estimating crude
incidence rates, defined as the number of PTLD events divided by the
person-years at risk accrued in that interval. To allow comparisons
with previously published estimates, the observed (O) number of PTLD
was compared with the expected (E) number of NHL in the general
population by applying age-, gender-, calendar year-, and
region-specific population-based incidence rates to the appropriate
person-years at risk.17 However, it should be recognized
that lymphoproliferative disorders after BMT are a unique set of
polyclonal and monoclonal tumors, and thus not directly comparable to
NHL in the general population. Kaplan-Meier methods were used to
calculate the cumulative probability of developing a
PTLD.18
Poisson regression methods for grouped survival data19 and
Cox proportional hazards regression techniques20 were used to compute estimates of relative risk (RR) of PTLD associated with
various patient-, treatment-, and transplant-related variables. These 2 approaches gave nearly identical results and only Poisson analyses are
presented. A forward step-wise selection procedure was used for
variable selection. Poisson models included stratification on time
since transplantation in 14 intervals to account for the sharp decline
in the patients at risk during the first year post-transplant. Monthly
cut-points were used during the first 9 months following transplantation, and at 1, 2.5, 5, 7.5, and 10 years thereafter. Models
were also stratified by the underlying disease for which the transplant
was performed using 5 categories: acute lymphoblastic leukemia (ALL),
acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML),
severe aplastic anemia, and other diseases. Patient-related variables
evaluated in multivariate models included cohort (IBMTR v
Seattle), geographic region, gender, age and calendar year of transplant, and primary disease. Transplant-related risk factors included degree of HLA match and donor relationship, conditioning regimen, use of antithymocyte globulin for conditioning, occurrence and
method of T-cell depletion, prophylaxis, or treatment for acute GVHD
with antithymocyte globulin or anti-CD3 monoclonal antibody 64.1 (Seattle only), all of which have been identified as risk factors for
PTLD in 1 or more prior studies.1-3 The occurrence and
treatment of acute GVHD (grades II to IV) and the occurrence of
extensive chronic GVHD were entered into the model as
time-dependent covariates. We also considered drugs commonly used
to prevent or treat acute GVHD. Tests of statistical significance were
2-sided and 95% likelihood-based confidence intervals (CIs) were calculated.
To account for the nonconstant relative hazard for several risk factors
over time since transplantation, we constructed a series of Poisson
regression models, each of which included risk factors plus interaction
terms. These interaction terms consisted of indicator variables (values
0, 1) that allowed for a step in the hazard function for a particular
risk factor at prespecified follow-up times (ie, 4, 5, 6, 7, 8, 9 months, and 1 year posttransplant). Because the 1-year cut-point
minimized the model deviance, these results will be presented in Table
3.
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RESULTS |
We identified 78 patients who developed PTLD, compared with 1.5 cases
of NHL expected in the general population (O/E = 51.5; 95%
CI, 40.7% to 64.3%). Sixty-four lymphoproliferative disorders occurred within the first year posttransplant (early-onset) while 14 arose 1 or more years after transplant (late-onset: range, 1 to 8.6 years posttransplant). Incidence was highest 1 to 5 months after
transplant (120 cases/10,000 patients/yr) (Table
2). The peak incidence (210 cases/10,000/yr) occurred during the third month posttransplant;
thereafter, a gradual but steep decline in the PTLD rate was observed,
with the lowest incidence occurring among 1-year survivors (<5 PTLD
cases/10,000/yr). The risk of late-onset PTLD remained significantly
higher than would be expected for de novo NHL in the general population
(O = 14, O/E = 12.8; 95% CI, 7.0% to 21.4%). The overall cumulative
incidence of PTLD was low, 1.0% ± 0.3% at 10 years. Although no
PTLD cases occurred among the 625 patients who survived more than 10 years post-BMT (Fig 1), only a small
percentage of these long-term survivors were recipients of family
mismatched, unrelated, or T-cell depleted bone marrow. The cumulative
incidence of PTLD exceeded the rate for invasive solid tumors in this
multiinstitutional cohort for nearly 5 years posttransplant (data for
solid cancers from Curtis et al21).
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| Fig 1.
Cumulative incidence (%) of PTLD (78 cases) and invasive
solid cancers (80 cases) following an allogeneic BMT;
multi-institutional cohort of 235 transplant centers. (Data for solid
tumors taken from Curtis et al.21)
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Most of the 64 recipients with early-onset PTLD had a primary disease
of leukemia, similar to the distribution in the entire cohort (16 ALL,
15 AML, 19 CML, 5 severe aplastic anemia, 5 myelodysplastic syndrome, 2 lysosomal storage disease, 1 Hodgkin's disease, and 1 hemoglobinopathy). EBV-related sequences were detected by in situ
hybridization in all 36 evaluable cases. Fifty-five (86%) patients
with PTLD died during the survey period; in 51 cases, the PTLD was the
primary (n = 39) or contributing (n = 12) cause of death. The diagnosis
of PTLD was made premortem in 39 cases and after death in 16. Disease
progression was rapid among the 39 patients diagnosed before death
(median survival, 0.6 months; range, 0.03 to 15 months). Nine patients
with early-onset PTLD are alive at a median follow-up duration of 88 months after PTLD diagnosis (range, 3 to 131 months).
Among 14 patients with late-onset PTLD, 13 had a diagnosis of leukemia
(5 ALL, 4 AML, 4 CML) and 1 had severe aplastic anemia. None of the
late-onset cases was evaluable for EBV status in the current study;
however, published case details indicate that 2 B-cell PTLD were
EBV-related,11,15 while 3 cases (1 B-cell and 2 T-cell
lymphomas) had no evidence of EBV-related sequences.12,13 Patients who developed late-onset PTLD had significantly longer survival after diagnosis than those with early-onset tumors (P = .03). Eleven of 14 patients (79%) with late-onset PTLD died; in 9 cases the lymphoma was either the primary (n = 8) or contributing (n = 1) cause of death. Two PTLD cases were diagnosed after death; median
survival for the 9 patients diagnosed before death was 6 months (range,
1 to 22 months). Three patients are alive at 37, 46, and 112 months
after developing PTLD.
Table 3 presents results from multivariate
models evaluating risk factors for PTLD diagnosed less than 1 year and
1 year posttransplant and for all time periods combined. The risk of early-onset PTLD was strongly associated (P < .0001) with
T-cell depletion of the graft (RR = 12.7), unrelated donor or 2
HLA-antigen mismatched related donor (RR = 4.1) and use of anti-CD3
monoclonal antibody 64.1 (RR = 43.2) or antithymocyte globulin (RR = 6.4) as prophylaxis or treatment of acute GVHD. A weaker association was observed with the occurrence of acute GVHD grades II-IV (RR = 1.9, P = .02). Recipients of transplants from 1 HLA-antigen mismatched related donors (RR = 1.9, P = .20) were not
significantly different in PTLD risk from those with HLA-identical
sibling grafts. Patients who received unrelated donor grafts (RR = 3.3)
had risks similar to those with 2 HLA-antigen mismatched related
transplants (RR = 4.8), and thus were grouped for analyses.
Among patients who survived more than 1 year posttransplant, the
relationship between PTLD risk and previously identified risk factors
(T-cell depletion, HLA disparity, use of antithymocyte globulin or
monoclonal antibody CD3 therapy) was greatly diminished (Table 3). The
only risk factor identified for late-onset PTLD was extensive chronic
GVHD (RR = 4.0, P = .01).
For all time intervals combined, conditioning regimens with radiation
were associated with risk of PTLD (RR = 2.9, P = .02). However,
only small numbers of PTLD patients (n = 4) did not receive radiation
and risk was inconsistent across geographic regions. Risk appeared to
vary by dose of fractionated TBI with 3.5- to 4.3-fold risks seen for
doses 13 Gy.
We compared the risk of PTLD associated with 5 different methods of
T-cell depletion of bone marrow (Table 4),
while controlling for other major risk factors. Significant differences
among T-cell depletion techniques were detected (test of homogeneity,
P = .009). Particularly high risks were seen for methods using
monoclonal antibodies specifically directed against T cells or T plus
NK cells (RR = 12.3) and for sheep red blood cell E-rosetting
techniques (RR = 15.6). Only 4 PTLD developed in recipients of grafts
depleted of T cells using CAMPATH-1 monoclonal antibodies, elutriation, or lectins, all of which remove both T and B cells.
We assessed the risk of PTLD related to the number of risk factors for
PTLD. Four major risk factors were defined: (1) T-cell depletion using
monoclonal antibodies directed at T cells or T plus NK cells, or
E-rosetting; (2) unrelated or 2 HLA-antigen mismatched related donor;
(3) prophylaxis or therapy for acute GVHD with antithymocyte globulin;
and (4) treatment of acute GVHD with anti-CD3 monoclonal antibody 64.1. Patients with unclassified or other methods of T-cell depletion were
excluded (84 patients and 2 PTLD cases). Figure
2 shows 10-year cumulative incidence rates
of PTLD in patients with 0, 1, 2, or 3 to 4 major risk factors, with
incidences ranging from 0.5% ± 0.3% in those with no major risk
factors to high rates among recipients with 2 and 3 major risk
factors (8.0% ± 2.9% and 22.3% ± 17.9%,
respectively). We observed significant heterogeneity among patients
with only 1 major risk factor (P = .0001). No PTLD developed
among 1,240 patients (1,412 person-years) with unrelated or 2
HLA-antigen mismatched related donor grafts who did not have other
major risk factors, and this group was not significantly different in
PTLD risk (P = .08) from those with no major risk factors (21 cases, 6/10,000/yr). This result contrasted with the substantial
increased risk seen among patients in other single-risk factor groups:
T-cell-depleted graft alone (14 cases, 71/10,000/yr) or antithymocyte
globulin therapy alone (7 cases, 27/10,000/yr). Of the 21 PTLD patients with no major risk factors, 20 received radiation for conditioning, 11 had acute or chronic GVHD (or both), and 3 received a graft that was
T-cell-depleted with CAMPATH-1 monoclonal antibodies or lectin
techniques.
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| Fig 2.
Cumulative incidence (%) of PTLD for patients with 0, 1, 2, or 3 to 4 major risk factors for PTLD. The 4 risk factors were
defined as: (1) T-cell depletion methods that selectively target T
cells or T + NK cells or E-rosetting; (2) unrelated or 2 HLA
antigen mismatched related donor; (3) antithymocyte globulin used as
prophylaxis or therapy for acute GVHD; and (4) anti-CD3 monoclonal
antibody 64.1 given as therapy for acute GVHD (Seattle only). Analysis
excludes 2 PTLD and 84 patients with unclassified or other methods of
T-cell depletion.
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Disease for which the transplant was performed and age at
transplantation had no significant association with risk of PTLD in
multivariate regression analyses. Drugs used for conditioning, evaluated singly and in combination, were also not significantly related to PTLD risk, and no increase in risk was observed for patients
who received antithymocyte globulin for conditioning (RR = 0.8, P = .68), as previously reported.2 There were no significant associations with specific immunosuppressive drugs used to
prevent or treat acute GVHD, other than those described above.
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DISCUSSION |
Lymphoproliferative disorders after bone marrow and organ
transplantation and among patients infected with AIDS are believed to
result from uncontrolled proliferation of EBV-transformed B-lymphocytes in the setting of immune dysfunction.1,22-28 Recent
evidence suggests that most of the latent EBV proteins, including
EBNA-1, -2, and -3, and LMP-1, are expressed on the malignant cells in EBV-induced PTLD1,4 and that LMP-1 functions as a signaling protein in these tumors.29 PTLD in the solid-organ
transplant setting have been extensively studied over the last 3 decades. A wide range of tumors, from lymphoid hyperplasias that
resolve after withdrawal of immunosuppression to aggressive monoclonal lymphomas with poor outcomes, are reported.9,30,31 In
contrast, lymphoproliferative disorders after allogeneic BMT have been
studied more recently.11,32 Most tumors after BMT appear to
be rapidly fatal, monoclonal or oligoclonal B-cell lymphomas that occur
early after transplant. Recent advances in the therapy of EBV-related lymphomas following BMT offer hope for improved survival following this
complication, and efforts have intensified to identify and monitor
patients at highest risk.33-35 Our current study evaluated 78 lymphoproliferative disorders occurring in a large cohort of 18,000 BMT recipients, and assessed incidence and risk factors for early-onset
versus late-onset PTLD.
Our 1.0% cumulative incidence of PTLD at 10 years after
BMT is comparable to rates of 0.5% to 1.8% reported from single
centers.2,11,36 Data from our study also demonstrate that
PTLD incidence varies markedly with time after transplantation, with
particularly high rates occurring during the first 5 months, followed
by a steep decline in incidence between 6 and 12 months posttransplant.
A significantly increased risk of PTLD continues among longer term survivors, although the rate is greatly diminished. The high incidence of PTLD during the first few months after transplant is consistent with
clinical investigations of the temporal pattern of immune reconstitution in marrow transplant recipients. Lucas et al reported that levels of anti-EBV cytotoxic T-lymphocyte precursors (CTLp) appear
to return to normal by 6 months posttransplant in most patients, and
that this interval of low CTLp frequency corresponds to the period of
highest risk of EBV-related PTLD.37 Although T-cell
immunity can be impaired in some patients for a prolonged interval,
most transplant recipients without chronic GVHD have substantial
recovery of T-cell function within 1 year.38,39 It is
perhaps not surprising then that PTLD incidence declines during the
first 12 months posttransplant from a high of 210 cases/10,000/yr to
less than 5 cases/10,000/yr.
Previous investigations of risk factors for lymphomas after BMT were
limited mostly to early-onset tumors.1-3,35,40 The 2 largest series evaluated 22 PTLD occurring among 2,150 BMT recipients at the University of Minnesota2 and 16 PTLD among 2,246 patients at Seattle.3 In those studies and the current
study, factors associated with severe immune dysfunction and altered
T-cell regulatory mechanisms were major predictors of early-onset
lymphomas. Significantly increased risks were seen with T-cell
depletion of the graft,2,3 unrelated donor or
donor-recipient HLA disparity,2,3 anti-CD3 monoclonal
antibody 64.1 therapy for acute GVHD,3 use of antithymocyte globulin,2,3 and transplantation for primary
immunodeficiency.2 New findings in the current study
indicate that the occurrence of acute GVHD of grades II to IV is
significantly related to risk of early-appearing PTLD and that patients
who receive 1 HLA-antigen mismatched related donor marrow are not
significantly different in risk from recipients of an HLA-identical
sibling graft. Radiation given as part of the conditioning regimen may
be an additional risk factor for PTLD, although there was inconsistency
in risk estimates across geographic areas. The mechanism by which
pretransplant radiation might contribute to the development of PTLD is
unclear. Higher TBI doses have been reported to increase GVHD
severity,41 and exaggerated acute GVHD may trigger the need
for prolonged immunosuppressive therapy, making it difficult to
quantify the relative contributions of these effects to PTLD risk.
Our study is the first to evaluate risk factors for late-onset PTLD
following allogeneic BMT, although case reports have described late-occurring lymphomas.3,12,13,15,42-44 Risk factors for early-onset PTLD in our study did not predict late-onset PTLD. However,
chronic GVHD, an established correlate of immune dysregulation in
long-term survivors, was identified as a strong risk factor. Patients
with chronic GVHD may also require long-term treatment with
immunosuppressive drugs, which is linked to an excess of PTLD following
solid-organ transplants.45 Thus, it is likely that immune
dysfunction and immunosuppressive mechanisms continue to play a role in
the development of PTLD among long-term survivors of BMT, although
different risk factors may be involved.
We found significant heterogeneity in PTLD risk among the nearly 2,500 patients who received T-cell-depleted grafts. Particularly high risks
were observed among recipients of grafts T-cell-depleted with
monoclonal antibodies or E-rosetting techniques that selectively target
T (or T plus NK) cells, whereas lower rates were associated with
methods that remove both T and B cells (CAMPATH-1 monoclonal antibodies, elutriation, lectins). Similarly, reports from single centers have described PTLD incidence rates as high as 25% in patients
depleted with T-cell-specific monoclonal antibodies or E-rosetting.2,5,11,40,46-48 In a recent multicenter study of 2,401 recipients T-cell-depleted with CAMPATH-1M or 1G, Hale et
al49 reported a low 1.1% cumulative risk of PTLD and
hypothesized that depletion of B cells, as well as T cells, may reduce
the viral load or virus target tissue in the interval before full recovery of the T-cell population. Low PTLD rates have been observed also after transplants using marrow that was T-cell-depleted with counterflow centrifugal elutriation50 or with lectin
agglutination/E-rosette-depleted grafts without additional
immunosuppression.4,35 Thus, the risk of PTLD appears much
less with T-cell depletion techniques removing both T and B
lymphocytes, possibly related to the reduced numbers of EBV-transformed
B lymphocytes.4
Although PTLD incidence is reported to increase to high levels (up to
25%) among patients with multiple risk factors,4,35 few
data are available to evaluate the individual and combined effects of
each of the PTLD risk determinants. Our results indicate a steep
increase in cumulative incidence with greater numbers of major risk
factors, each of which are markers of altered immunity or T-cell
function. In previous studies, patients receiving unrelated or
HLA-mismatched related donor transplants were reported to be at higher
risk of PTLD than those with HLA-identical sibling
donors,2,3,32,37,46,47 although most patients in these
investigations received a T-cell-depleted graft or other T-cell
manipulation. Our study evaluated recipients of an unrelated or 2
HLA-antigen mismatched related graft who had no other major risk
factors and found a low PTLD risk. This result contrasts with elevated
PTLD rates among patients who received antithymocyte globulin alone or
T-cell-depleted grafts alone (no other major risk factors). Although
caution is indicated due to the high early mortality rate after HLA
mismatched transplants and the strong correlation between HLA disparate
donors and other risk factors, such as acute GVHD, these results
suggest that HLA incompatibility by itself may be less important than
other variables affecting PTLD risk. Along with the factors considered
in the current study are other variables that appear to influence
susceptibility to EBV-related lymphoproliferative disorders in
solid-organ and marrow transplants, such as EBV viral burden, specific
EBV strain (EBER A v EBER B), and deficiencies in cellular
immunity to EBV.4,33,37,51 Even patients with no
identifiable risk factors, except possibly radiation, may develop PTLD,
although the risk is relatively low, reflecting variability in immune
reconstitution not accounted for by known determinants.
Early-onset PTLD in our series were uniformly EBV-positive and most
developed progressive disease that proved rapidly fatal. The 14 patients with late-onset PTLD had a significantly longer survival
postdiagnosis than those with early-onset tumors. In addition, 3 of the
late-onset PTLD cases in our series were described in published reports
to be EBV-negative and 2 were T-cell PTLD.12,13 Recent
evidence from solid-organ transplants suggests that EBV-negative PTLD
are morphologically and clinically distinct from EBV-positive PTLD;
EBV-negative PTLD after organ transplants tended to have later onset
(median, 4.9 years), a higher prevalence of monomorphic lymphomas, and
a greater proportion derived from T cells.52 These
differences indicate the need for further research to fully characterize the clinicopathologic features of late-onset PTLD following BMT.
Most patients in our study developed PTLD during the 1980s and early
1990s, when available treatments (ie, antiviral and chemotherapeutic agents) were largely ineffective. Underreporting of PTLD during this
period may be substantial due to difficulties in diagnosis, so that our
estimates of PTLD incidence are likely to be conservative. In
recent years, considerable progress has been made in the diagnosis, prevention, and treatment of PTLD among allogeneic BMT recipients. Immunovirologic assays are available to detect high levels of EBV DNA,
which strongly correlates with increased risks of EBV-related PTLD.33,53,54 New approaches for prophylaxis and treatment have been reported, including successful therapy with infusions of
donor leukocytes.35 Recent promising strategies include
antiviral prophylaxis and treatment with gene-marked EBV-specific T
lymphocytes,34,55 and the use of specific anti-CD21 and
anti-CD24 murine monoclonal antibodies to control severe
PTLD.56 These advances may improve the prognosis for
patients at increased risk of PTLD.
We conclude from these analyses in a large cohort of BMT recipients
that the risk of PTLD persists among patients surviving more than 1 year after transplant, although it is greatly decreased compared with
the early posttransplant period. Moreover, our data indicate that risk
factors associated with altered immunity and T-cell regulatory
mechanisms are predictors of both early- and late-onset PTLD. Patients
at highest risk of PTLD are candidates for trials of prophylactic or
preemptive therapies.
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APPENDIX |
This research is supported by Contracts No. CP-51027 and CP-51028 from
the National Cancer Institute. The International Bone Marrow Transplant
Registry is supported by Public Health Service Grant no. PO1-CA-40053
from the National Cancer Institute, the National Institute of Allergy
and Infectious Diseases, and the National Heart, Lung and Blood
Institute of the US Department of Health and Human Services; and grants
from Alpha Therapeutic Corp; Amgen, Inc; Anonymous; Baxter Healthcare
Corporation; Bayer Corp; Berlex Laboratories; Blue Cross and Blue
Shield Association; Lynde and Harry Bradley Foundation; Bristol-Myers
Squibb Co; Cell Pro, Inc; Centeon; Center for Advanced Studies in
Leukemia; Chimeric Therapies; Chiron Therapeutics; Charles E. Culpeper
Foundation; Eleanor Naylor Dana Charitable Trust; Eppley Foundation for
Research; Genentech, Inc; Glaxo Wellcome Co; ICN Pharmaceuticals;
Immunex Corp; Kettering Family Foundation; Kirin Brewery Company;
Robert J. Kleberg, Jr and Helen C. Kleberg Foundation; Herbert H. Kohl Charities, Inc; Nada and Herbert P. Mahler Charities; Milstein Family
Foundation; Milwaukee Foundation /Elsa Schoeneich Research Fund;
NeXstar Pharmaceuticals, Inc; Samuel Roberts Noble Foundation; Novartis
Pharmaceuticals; Ortho Biotech, Inc; John Oster Family Foundation; Jane
and Lloyd Pettit Foundation; Alirio Pfiffer Bone Marrow Transplant
Support Association; Pfizer, Inc; Pharmacia and Upjohn; Principal
Mutual Life Insurance Co; RGK Foundation; Rockwell Automation Allen
Bradley Co; Roche Laboratories; SangStat Medical Corp; Schering-Plough
Oncology; Searle; Stackner Family Foundation; Starr Foundation; Joan
and Jack Stein Foundation; SyStemix; United Resource Networks; and
Wyeth-Ayerst Laboratories. The Fred Hutchinson Cancer Research Center
investigators are supported by Grants No. P01-CA 18029, P01-CA-18221
and P01-CA-15704 from the National Cancer Institute, and P01-HL-36444
from the National Heart, Lung, and Blood Institute.
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ACKNOWLEDGMENT |
We are indebted to all collaborating investigators and staff from the
participating transplant centers who contributed data to this study. We
wish to thank Muriel Siadek, K. Erne, and Gary Schoch from Fred
Hutchinson Cancer Research Center, Seattle, and Diane Knutson and
Sharon Nell from the IBMTR, Milwaukee, for support in data collection.
We acknowledge Kathy Chimes, Elena Adrianza, Andy Singer, and Diane
Fuchs from Westat, Inc for coordination of field studies, George Geise
and Christel McCarty from Information Management Services for computing
support, and Denise Duong and Rebecca Albert for manuscript preparation.
| |
FOOTNOTES |
Submitted February 10, 1999; accepted May 26, 1999.
See Appendix for grant support information.
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.
This is a US government work. There are no restrictions on its use.
Address reprint requests to Rochelle E. Curtis, MA,
Executive Plaza South, Room 7042, National Cancer Institute, Bethesda,
MD 20892; e-mail: curtisr{at}epndce.nci.nih.gov.
| |
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TOP
ABSTRACT
INTRODUCTION