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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Departments of Hematology, Statistics,
Virology, and Medical and Tumor Immunology, University Hospital
Rotterdam/Daniel den Hoed Cancer Center, The Netherlands; Departments
of Hematology and Virology, University Medical Center Utrecht, The
Netherlands; Clinic of Bone Marrow Transplantation, University Hospital
Essen, Germany; and Department of Hematology, Ospedale San Martino,
Genoa, Italy.
Reactivation of the Epstein-Barr virus (EBV) after allogeneic
stem cell transplantation (allo-SCT) may evoke a protective cellular
immune response or may be complicated by the development of
EBV-lymphoproliferative disease (EBV-LPD). So far, very little is known
about the incidence, recurrence, and sequelae of EBV reactivation
following allo-SCT. EBV reactivation was retrospectively monitored in
85 EBV-seropositive recipients of a T-cell-depleted (TCD) allo-SCT and
65 EBV-seropositive recipients of an unmanipulated allo-SCT. Viral
reactivation (more than 50 EBV genome equivalents [gEq]/mL) was
monitored frequently by quantitative real-time plasma polymerase chain
reaction until day 180 after SCT. Probabilities of developing viral
reactivation were high after both unmanipulated and TCD-allogeneic SCT
(31% ± 6% versus 65% ± 7%, respectively). A high
CD34+ cell number of the graft appeared as a novel
significant predictor (P = .001) for EBV reactivation.
Recurrent reactivation was observed more frequently in recipients of a
TCD graft, and EBV-LPD occurred only after TCD-SCT. High-risk status,
TCD, and use of antithymocyte globulin were predictive for developing
EBV-LPD. Plasma EBV DNA quantitatively predicted EBV-LPD. The positive
and negative predictive values of a viral load of 1000 gEq/mL were,
respectively, 39% and 100% after TCD. Treatment-related mortality did
not differ significantly between TCD and non-TCD transplants, but the
incidence of chronic graft-versus-host disease was significantly less
in TCD patients. It is concluded that EBV reactivation occurs
frequently after TCD and unmanipulated allo-SCT, especially in
recipients of grafts with high CD34+ cell counts. EBV-LPD,
however, occurred only after TCD, and EBV load quantitatively predicted
EBV-LPD in recipients of a TCD graft.
(Blood. 2001;98:972-978) Epstein-Barr virus-associated lymphoproliferative
disease (EBV-LPD) is a serious complication of allogeneic stem cell
transplantation (allo-SCT) and solid-organ
transplantation.1-3 Although the incidence of EBV-LPD is
generally less than 2% after allo-SCT, it may increase to 20% in
patients with established risk factors, such as unrelated donor SCT,
the use of T-cell-depleted (TCD) allografts, use of antithymocyte
globulin (ATG), and immunosuppression for prevention and treatment of
graft-versus-host disease (GVHD).4-8 EBV-LPD is associated
with a poor prognosis despite the use of anti-B-lymphocyte monoclonal
antibody therapy,9-12 donor lymphocyte infusion
(DLI),13 and infusion of EBV-specific cytotoxic T
cells.14,15 Therefore, early diagnosis and preventive
measures, such as B-cell depletion of the donor
graft,4,7,16 and pre-emptive therapy may be clinically
useful.17-24
We developed a real-time polymerase chain reaction (PCR) assay
for the quantitative detection of EBV-DNA in plasma.25 The assay accurately monitors viral load in plasma from patients with infectious mononucleosis and immunocompromised patients at risk of
EBV-LPD or with established EBV-LPD.25,26 In contrast to cytomegalovirus (CMV) antigenemia after allo-SCT and the risk of
developing CMV disease, little is known about reactivation of EBV
during the first 3 to 6 months after allo-SCT and the predictive value
of EBV reactivation for subsequent EBV-LPD. Although several studies
have shown an association between viral load and a diagnosis of
EBV-LPD,27-43 no study has longitudinally followed a
larger cohort of allo-SCT recipients with multiple risk factors. We set out to monitor EBV reactivation by real-time PCR at regular intervals after allo-SCT. Incidences, risk factors, and sequelae of EBV reactivation were compared between patients receiving a TCD-SCT and
patients having transplantation with an unmanipulated stem cell graft.
We show that subclinical EBV reactivation is a very frequent event
after allo-SCT and that quantification of EBV-DNA appears useful to
identify patients at risk of progression to overt EBV-LPD.
Patients
Transplantation
Partial T-cell depletion was performed using sheep erythrocyte
rosetting (n = 53) or CD34 selection (Cellpro, Wezembeek, Belgium) (n = 32). Median T-cell numbers differed more than 2 logs between TCD
and unmanipulated grafts (2.0 × 105/kg versus
510 × 105/kg), but numbers of granulocyte-macrophage
colony-forming units (CFU-GMs) and CD34+ mononuclear cells
(MNCs) did not differ significantly between the groups of patients.
Peripheral blood-derived stem cells were used relatively more often
than bone marrow-derived stem cells in patients receiving a TCD graft
as compared with patients receiving an unmanipulated graft
(P < .01). Graft-versus-host (GVH) prophylaxis was
cyclosporin A (3 mg/kg) from day All patients received ciprofloxacin and fluconazole for prevention of infection during neutropenia, and cotrimoxazole was given after neutrophil recovery until days 180 to 360 after SCT. Patients having transplantation in Utrecht (TCD-SCT) and Genoa (non-TCD-SCT) received long-term acyclovir prophylaxis from day 0 until day 360. Erythrocyte and platelet products for transfusion were filtered to remove leukocytes and subsequently irradiated (25 Gy). Patients were hospitalized in reverse isolation in rooms with high-efficiency particulate-filtered air. All patients received food with a low microbial count until discharge, and parenteral alimentation was given in case of severe mucositis. Real-time Taqman assay Taqman PCR primers were selected from the EBV-DNA genome encoding for the nonglycosylated membrane protein BNRF1-p143 and generated a DNA product of 74 base pairs, as described before.25 A known EBV-DNA copy number based on a reference standard quantified by electron microscopy (ABI Advanced Biotechnologies, Columbia, MA) was used for standardization. Serial dilutions ranging from 10 to 107 EBV-DNA genome equivalents per milliliter (gEq/mL) were made to characterize linearity, precision, specificity, and sensitivity. The Taqman assay appeared to detect viral DNA in plasma over a linear span between 50 and 107 gEq/mL, with an average coefficient of variation of 1.56% (range, 0.7% to 7.0%). Test results below 50 gEq/mL were considered negative. No viral DNA was detected in plasma of healthy EBV-seropositive individuals.25 EBV reactivation was defined as a plasma EBV-DNA level exceeding 50 gEq/mL. Recurrent reactivation was defined by a positive PCR (more than 50 gEq/mL) after (at least) 2 consecutive negative PCR results following a preceding episode of reactivation. Viral load was monitored in blood samples drawn at 2-week intervals starting at SCT until day 180 after SCT.EBV-LPD diagnosis A diagnosis of EBV-LPD was preferably based on lymph node histology or cytology and was classified according to the criteria of Knowles et al.44 Immunohistology included antibody staining with CD19-specific (Becton Dickinson, San Jose, CA), CD20-specific (Dako, Glostrup, Denmark), and EBV latent membrane protein-1-specific (Dako) monoclonal antibodies. Furthermore, clonality was assessed using immunohistochemical staining with monoclonal antibodies to kappa and lambda light chains (Dako). In situ hybridization was performed to detect EBV-encoded small RNA molecules (EBV-EBER) using an EBV-EBER probe (Dako) and PCR for detection of EBV-DNA encoding for the BamHI fragment. EBV-LPD staging included physical examination, whole-body computed tomography (CT) scanning, and flow cytometric detection of monoclonal B lymphocytes in blood, bone marrow, and, if indicated, cerebrospinal fluid.End points and statistical analysis The data were analyzed as of January 2000. Patient characteristics of non-TCD patients and TCD patients were compared using Fisher exact test or Pearson chi-square test, whichever was appropriate, in case of discrete variables, or the Wilcoxon rank-sum test in case of continuous variables. End points of the study included time to EBV reactivation, EBV-LPD, acute GVHD grades II to IV, chronic GVHD, and treatment-related mortality (TRM). Time to first EBV reactivation was determined from the date of transplantation until day 180, and patients were censored at the date of last serum sample if this sample had been taken before day 180. Time to EBV-LPD was measured from SCT until EBV-LPD. Patients who died without EBV-LPD were censored at the date of death. Patients still alive at the date of analysis were censored at the last follow-up date. Two EBV-seronegative donor-recipient pairs were excluded from the analysis of EBV reactivation and EBV-LPD. GVHD was diagnosed and graded according to consensus criteria.45 Chronic GVHD was evaluated among patients who survived at least 100 days after transplantation. TRM was defined according to standard criteria.46 Time to EBV reactivation, EBV-LPD, acute and chronic GVHD, and TRM were estimated by the Kaplan-Meier method, and Kaplan-Meier curves were generated to illustrate differences between subgroups of patients.47 The following variables were included in the analysis of prognostic factors: sex, male patient and female donor, age, risk status, donor (sibling versus matched unrelated donor), source of stem cells (bone marrow versus peripheral blood), type of transplant (non-TCD versus TCD without ATG versus TCD with ATG), and graft characteristics (number of MNCs, number of CD34+ cells, number of CD3+ and CFU-GMs infused). Univariate survival analysis was performed using the log-rank test and Cox regression to see whether there was a difference between subgroups.48,49 The variables that appeared significant in the univariate analysis were also included in a multivariate Cox regression. Moreover, Cox regression was performed using EBV reactivation within day 180 as a time-dependent covariate to assess whether EBV reactivation predicted EBV-LPD and TRM. All reported P values are 2-sided, and a significance level of = .05 was used.
EBV reactivation The probability of developing EBV reactivation was greater after TCD-allogeneic SCT than after non-TCD-SCT (Figure 1, Table 2). That difference, however, could be largely attributed to the use of ATG in conjunction with TCD (Figure 1, Table 3). Probabilities of viral reactivation were not different between recipients of a non-TCD-SCT and recipients of a TCD-SCT without concomitant ATG. Median time to first reactivation was 58 days (range, 5-180 days) in the TCD group and 63 days (range, 2-107 days) in the non-TCD group (not significant). Plasma EBV-DNA levels measured at the peak of the first reactivation did not differ between the groups. Recurrent reactivation was significantly more frequent after TCD (Table 2): 14 of 85 patients (16%) experienced multiple episodes of EBV reactivation after TCD-SCT, including 8 patients with 2 episodes, 5 patients with 3 episodes, and 1 patient showing 4 distinct periods of reactivation. This is exemplified for a recipient of a TCD donor graft who experienced 3 episodes of EBV reactivation without developing EBV-LPD (Figure 2). In contrast, only 2 of 65 patients (3%) receiving non-TCD grafts had a second period of reactivation. ATG appeared not to be associated with recurrent reactivation, as only 2 of 14 patients with recurrent reactivation after TCD also received ATG as part of the conditioning regimen. Several risk factors predicted first reactivation in univariate analysis (Table 3), including TCD (P = .02), use of ATG in the conditioning regimen (P < .001), transplantation of an unrelated donor graft (P = .02), and a high CD34+ cell number of the graft (P = .001) (Figure 3). Following multivariate analysis, only the use of ATG and a high CD34+ cell count (> 1.35 × 106/kg) remained independently associated with EBV reactivation (Table 3). Numbers of CD34+ and CD3+ cells were not associated with each other.
EBV-LPD EBV-LPD was observed only after TCD-SCT (Table 2, Figure 4). Five patients developed EBV-LPD after HLA-identical sibling SCT and 5 after unrelated donor SCT (Table 4). Five of these patients had received ATG before unrelated donor SCT, and 9 of them had been treated for high-risk disease. All EBV-LPD donor-recipient pairs were EBV seropositive. One donor had negative EBV serology before transplantation. Median time from first reactivation to EBV-LPD was 22 days (range, 13-120 days) (Table 2). Median EBV-DNA level at EBV-LPD diagnosis was 110 000 gEq/mL (range, 1800-790 000 gEq/mL). Histologic proof of a diagnosis of EBV-LPD and classification according to the criteria of Knowles et al44 were obtained in 8 patients. Patient 8 (Table 4), who received an HLA-identical sibling SCT for multiple myeloma, was diagnosed with EBV-LPD by the presence of monoclonal B cells in his cerebrospinal fluid and an elevated plasma EBV-DNA level. Patient 9, who received an unrelated donor SCT because of SAA, was diagnosed with EBV-LPD because of massive lymphadenopathy on CT scanning and a highly elevated plasma EBV-DNA level. Six patients received anti-B-cell monoclonal antibody therapy (rituximab), 5 patients received DLI, and immune suppression was discontinued in 8 patients (Table 4). Five patients obtained a complete remission and 5 other patients died of progressive EBV-LPD. Two responding patients are currently alive with a follow-up of 620 and 351 days. Three responding patients developed severe GVHD, 2 following DLI, and died of GVHD-related complications. Use of ATG, application of TCD, and high-risk status of underlying disease significantly predicted EBV-LPD in univariate analysis. Multivariate analysis was not performed because the latter 3 variables appeared strongly associated and the small number of events did not allow a reliable multivariate analysis.
Several risk factors occurring after SCT were evaluated for a possible
association with EBV-LPD by time-dependent analysis. A lower lymphocyte
count at first EBV reactivation appeared not predictive for developing
EBV-LPD. In contrast, EBV load significantly predicted EBV-LPD in a
quantitative manner. A stepwise increase of EBV-DNA by 1 log (Table
5) yielded a hazard ratio (HR) of 2.9 (95% confidence interval [CI], 1.7-4.8) for those patients receiving
a TCD graft (P < .001). Numbers of patients with a
TCD-SCT with plasma levels of EBV DNA exceeding a certain threshold
value and the corresponding positive and negative predictive values for
EBV-LPD for that subset of patients are shown in Table 5. Although the
positive predictive value was 24% for patients with a copy number of
100 gEq/mL or higher, it rose to 100% at the level of 500 000
gEq/mL. However, only one patient with EBV-LPD reached that high
number, and consequently the negative predictive value was 89%.
Graft-versus-host disease The actuarial probability of acute GVHD grade II to IV at day 100 was 57% ± 4% for the whole group and was not significantly different for patients receiving a TCD graft as compared with patients receiving unmanipulated allo-SCT. An unrelated donor graft and a high CD34+ cell count of the graft (independent of the number of CD3+ T cells in the graft) were the only significant risk factors for developing acute GVHD following multivariate analysis. EBV reactivation was not associated with acute GVHD. Actuarial probabilities of chronic limited and extensive GVHD at 12 months after SCT were significantly higher for non-TCD patients (83% ± 5%) than for TCD patients (38% ± 6%) (P < .001).Treatment-related mortality The actuarial probability of TRM was 29% ± 4% at 1 year for all patients and did not differ between TCD and unmanipulated allo-SCT. Higher age and a higher CD34+ cell count (> 1.35 × 106/kg) of the graft predicted higher TRM in multivariate analysis. Following time-dependent analysis, EBV reactivation (HR 1.9; 95% CI, 1.0-3.3; P = .04) and acute GVHD grade II to IV (HR 1.8; 95% CI, 1.0-3.3; P = .05) were associated with higher TRM. In addition, a higher lymphocyte count (> 0.6 × 109/L) at the time of first EBV reactivation significantly predicted less TRM (HR 0.3; 95% CI, 0.1-0.8; P = .02).
This study demonstrates that EBV reactivation is a very frequent event after both TCD and unmanipulated allo-SCT. In particular, recipients of stem cell grafts with high numbers of CD34+ MNCs appeared to be at risk for EBV reactivation. However, patients receiving a TCD-SCT were at significantly higher risk for recurrent reactivation, and only these patients developed EBV-LPD. The development of impending EBV-LPD in these patients could be predicted quantitatively by monitoring viral load in plasma at regular intervals during the first 6 months after SCT. EBV reactivation was observed frequently after TCD-SCT and after unmanipulated allo-SCT as well. The high incidence of first EBV reactivation after TCD-SCT could be largely attributed to the use of ATG and, as a result, TCD per se did not appear to be an independent risk factor for early EBV reactivation. However, patients receiving a TCD-SCT showed more recurrence of reactivation, and EBV-LPD was observed only after TCD. Because the conditioning regimen has eradicated autologous EBV-specific immunity after both TCD and unmanipulated SCT, early EBV reactivation may occur after both modes of allo-SCT.50,51 However, the significantly higher risks for recurrent EBV reactivation and EBV-LPD in TCD-SCT as compared with unmanipulated SCT may be explained by the impaired capacity of patients receiving TCD grafts to mount an effective immune response to the reactivating virus. The strongly reduced numbers of EBV-specific memory T cells in TCD as compared with unmanipulated grafts may play a major role in this respect.52,53 Apart from the use of ATG as part of the conditioning regimen, we
identified the number of CD34+ cells in the graft as a
novel independent risk factor for developing EBV reactivation (Table 3,
Figure 3), and also for acute GVHD and TRM. Przepiorka et
al54 recently reported that recipients of peripheral blood
stem cell grafts with high CD34+ cell counts were at higher
risk for acute GVHD, an effect that appeared independent of the number
of CD3+ T cells. They suggested that GVHD at high
CD34+ cell doses may be exacerbated by cytokines released
by the markedly expanding myeloid population at the time of
engraftment. This explanation is supported by high levels of
proinflammatory cytokines in patients with severe
GVHD.55-57 In the present study, acute GVHD significantly
predicted TRM in a time-dependent analysis. Therefore, the association
of CD34+ cell dose and TRM might be explained by an
increased incidence of GVHD. The association of CD34+ cell
dose and EBV reactivation, however, is less likely to be explained by
more GVHD, because EBV reactivation preceded the onset of acute GVHD in
a significant number of patients. Alternative explanations may include
infusion of a higher number of EBV-infected B cells together with
larger stem cell grafts, or stimulation of B-cell proliferation by
cytokines produced by the higher number of rapidly maturing myeloid
progenitors. The latter explanation is supported by a number of
preclinical as well as clinical studies showing that proinflammatory
cytokines, such as interleukin-1 (IL-1), tumor necrosis factor- A number of studies have demonstrated a correlation between high levels of viral load and a diagnosis of EBV-LPD after both SCT and solid-organ transplantation.26-43 No study, however, has longitudinally followed allo-SCT recipients with multiple risk factors from day 0 until day 180 and reported positive and negative predictive values. Lucas et al41 evaluated the predictive value of quantitative PCR using DNA extracted from peripheral blood MNCs in a cohort of 195 patients receiving solid-organ transplantation. Although the negative predictive value appeared very high (100%), the positive predictive value was 38%. Our results observed in recipients of an allo-SCT are in line with these findings. Considering both TCD and non-TCD transplants, the negative and positive predictive values of a copy number of 1000 gEq/mL were, respectively, 100% and 28%. Higher predictive values were obtained when the analysis was restricted to patients receiving a TCD-SCT. The positive predictive values of a high EBV-DNA level of more than 1000 gEq/mL and more than 10 000 gEq/mL for patients receiving TCD-SCT were 39% and 50%, respectively (Table 5). Although highly significant, these predictive values also indicate that
most patients (even recipients of TCD grafts) were able to mount an
effective immune response and clear their viral reactivation.
Monitoring of the reconstitution of HLA-specific T lymphocytes may add
to the predictive value of viral load quantification. For this purpose,
rapid assays are now available, such as the enumeration of EBV-specific
T lymphocytes by tetramer binding or the induction of intracellular
interferon-
We thank Judith Guldemeester and Barbara Bruno for expert technical assistance and Janine Vrij for outstanding secretarial work.
Submitted December 6, 2000; accepted April 16, 2001.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Jan J. Cornelissen, Department of Hematology, University Hospital Rotterdam/Daniel den Hoed Cancer Center, Groene Hilledijk 301, 3075 EA Rotterdam, The Netherlands; e-mail: cornelissen{at}hemh.azr.nl.
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P. Meij, J. W. J. van Esser, H. G. M. Niesters, D. van Baarle, F. Miedema, N. Blake, A. B. Rickinson, I. Leiner, E. Pamer, B. Lowenberg, et al. Impaired recovery of Epstein-Barr virus (EBV)--specific CD8+ T lymphocytes after partially T-depleted allogeneic stem cell transplantation may identify patients at very high risk for progressive EBV reactivation and lymphoproliferative disease Blood, June 1, 2003; 101(11): 4290 - 4297. [Abstract] [Full Text] [PDF]
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M. I. Gutierrez, M. M. Ibrahim, J. K. Dale, T. C. Greiner, S. E. Straus, and K. Bhatia Discrete Alterations in the BZLF1 Promoter in Tumor and Non-Tumor-Associated Epstein-Barr Virus J Natl Cancer Inst, December 4, 2002; 94(23): 1757 - 1763. [Abstract] [Full Text] [PDF]
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J. W. J. van Esser, H. G. M. Niesters, B. van der Holt, E. Meijer, A. D. M. E. Osterhaus, J. W. Gratama, L. F. Verdonck, B. Lowenberg, and J. J. Cornelissen Prevention of Epstein-Barr virus-lymphoproliferative disease by molecular monitoring and preemptive rituximab in high-risk patients after allogeneic stem cell transplantation Blood, May 29, 2002; 99(12): 4364 - 4369. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
3 until day +100 after TCD-SCT, and
the combination of methotrexate (15 mg/m2 on day 1; 10 mg/m2 on days 3, 6, and 11) and cyclosporin A was used in
recipients of an unmanipulated SCT.
, and IL-6, may very effectively stimulate the growth of
EBV-infected B cells.
in T cells after specific stimulation.
surveillance of viral activity during treatment with different immunosuppressive agents.
Transpl Int.
1996;9:439-445