Fatal problems encountered in allogeneic stem cell transplantation include EBV reactivation and post transplant lymphoproliferative disorders (PTLDs) with high mortality rates. We performed a retrospective analysis in all consecutive adult and pediatric EBV reactivations and PTLD during a period of 8.5 years. There were 26 patients with EBV reactivation/PTLD out of a total of 854 transplantations giving an overall incidence of 3.0%. Specifically, the incidence of EBV-PTLD was 1.3%, whereas that of EBV reactivation was 1.8%. Median age was 46.0 and 11.0 years in the adult and pediatric patients, respectively. There were high rates (54%) of concomitant bacterial, viral, fungal and parasitic infections at the time of EBV manifestation. Variable treatment regimens were applied including in most cases an anti-CD20 regimen often in combination with virustatic compounds, polychemotherapy or donor lymphocytes. The mortality rates were 9 of 11 (82%) in patients with EBV-PTLD and 10 of 15 (67%) in patients with reactivation. Only 7 of 26 patients (27%) are alive after a median follow-up of 758 days (range 24–2751). The high mortality rates of EBV reactivation and of EBV-PTLD irrespective of multimodal treatment approaches emphasize standardization and optimization of post transplant surveillance and treatment strategies to improve control of these often fatal complications.
Although supportive strategies in the period following allogeneic SCT have improved tremendously in recent years, many problems remain poorly controlled. A persisting danger for the recipients of allogeneic SCT is post transplant lymphoproliferative disorders (PTLD), mostly caused by EBV. Mortality rates were reported to be as high as 50–90%.1, 2 Although PTLD was reported to occur in <1% of all transplantation cases, higher rates might be seen in the presence of specific risk profiles such as intensive immunosuppression or T-cell depletion.3, 4
In stem cell recipients, a separation of EBV-associated PTLD according to the time of onset either in the early post transplantation period (<1 year) or with a late manifestation (>1 year) was suggested, as the latter cases are frequently EBV negative and are even worse prognostically.5 Whether a negative EBV status which is found in ∼20% of all PTLD cases6 is associated with more aggressive courses7, 8, 9 is still controversial.
Various therapeutic approaches were suggested for EBV-associated PTLD including anti-B-cell treatments such as rituximab. Severe cases may require cytotoxic polychemotherapy, for example according to the CY, hydroxydaunorubicin, oncovin and prednisolone (CHOP) protocol.9 Immunotherapeutic strategies are based on adoptive immunotherapy by reduction or withdrawal of immunosuppression or donor lymphocytes (DLIs). Others advise the use of EBV-specific cytotoxic T cells.4, 10, 11 However, response to these different treatment modalities is frequently poor. As viral reactivation, progression to EBV-PTLD and subsequent mortality are conceived as a continuous process, diverse strategies have been suggested to prevent this cascade. Frequent molecular monitoring of the EBV load and anti-CD20 antibody therapy for cases at high risk have been suggested.12, 13, 14
To further determine the incidence, outcome, risk profiles and clinical characteristics of EBV reactivations and PTLD in the post transplant period, we here performed a retrospective study in all 854 patients who received allogeneic SCT between January 1999 and June 2007 in the University Hospital of Hamburg, Germany, and performed further characterization of the 11 cases with EBV-associated PTLD and of the 15 cases with EBV reactivation.
Patients and methods
In the period of study, 854 adult and pediatric patients had received allogeneic SCT at the University of Hamburg-Eppendorf, Germany. A diagnosis of EBV-associated PTLD was obtained in 11 patients and EBV reactivation in 15 cases. Patients with EBV-negative PTLD were excluded from the analysis. Also, two patients with the phenomenon of EBV-associated hemophagocytic lymphohistiocytosis (HLH) were excluded from the study, although they showed EBV reactivation after allogeneic SCT due to the different condition of the disease.
Monitoring of the serum EBV-DNA load was performed weekly by semiquantitative PCR (from 1999 to 2001) and by quantitative assessment (from 2002) in the early post transplant period within the first 4 weeks from transplantation. Measurement of the peripheral viral load was performed with a range of one to four analyses per patient at the time of EBV manifestation. When several results were available in one patient, the highest viral load was being taken for further studies. Afterward, molecular EBV diagnostics were performed when there were unexplained fever, lymphadenopathy or other suspicious symptoms.
At the period of study, there were no clear-cut definitions for EBV reactivation and PTLD in the literature available. Patients were therefore treated for EBV reactivation when there was any occurrence of PCR positivity for EBV-DNA in serum as previously described,15 and when there was no sign of lymphoproliferative disease. EBV-associated PTLD was diagnosed in cases with clinical or radiological signs of lymphadenopathy in coincidence to EBV-DNA positivity in the serum.
Characterization of transplantation
The 26 transplants were performed from 1 antigen-mismatched related donor (MMRD), 2 from matched related donors (MRD), 13 from HLA-matched unrelated donors (MUD) and 10 from HLA-mismatched unrelated donors (MMUD). Donors were required to match the recipients for HLA-A, -B, -DRB1 and -DQB1. In total, 13 SCTs were preceded by reduced intensity conditioning (RIC) and 13 by standard conditioning strategies. Transplants were performed by BM in 12 patients (46%) and by PBSC in 14 cases (54%) with a median of 5.6 × 106 CD34+ stem cells per kg body weight (range 2.0–15.0).
The EBV serostatus was available in 21 recipient/donor pairs and was similar in 15 of 21 transplants and different in 6 other transplant cases. Considering the seven adults who developed PTLD, four patients received RIC and three had standard conditioning regimens, whereas all four pediatric patients with PTLD received standard conditioning. All patients received antithymocyte globulin (ATG) as part of the preparative regimen. Prophylaxis of GVHD consisted in most cases of CsA either with MTX or mycophenolate mofetil (MMF). CsA was continued from day −1 up to 6 months post transplantation (adjusted to serum levels of 140–220 ng/ml). MTX (10 mg/m2) was administered on days +1, +3 and +6. Acute GVHD (aGVHD) and regimen-related toxicity were graded as previously published.16, 17, 18
Patients stayed in high efficiency particulate air-air filtered single rooms during the time of neutropenia. G-CSF was usually started on day +5 and continued until stable engraftment. Immune globulins (i.v.) were administered on a regular schedule within the first 3 months post transplant. Prophylaxis consisted of ciprofloxacin and metronidazole for bacterial and itraconazole or voriconazole for fungal infections. Pneumocystis jirovecii prophylaxis was done by weekly cotrimoxazole on 2–3 consecutive days or by monthly aerosolized pentamidine. Acyclovir was continued as herpes prophylaxis up to day +180. Monitoring of blood for CMV antigen was performed by PCR once weekly. Ganciclovir was the treatment of choice in case of CMV reactivation/infection (2 × 5 mg/kg daily). In cases with high CMV load, therapy was continued for 14 days with 1 × 5 mg/kg ganciclovir daily. Persistent CMV antigenemia was treated with foscavir (3 × 60 mg/kg daily).
A total of 26 patients had EBV reactivation/PTLD during the study period. There were 15 patients with EBV reactivation and 11 with EBV-PTLD. Median age was 46 years (range 17–66) and 11 years (range 1–15) in the adult and pediatric patients (Table 1). Clinical symptoms in the PTLD patients were lymphadenopathy (8 of 11; 73%), fever (5 of 11; 45%), splenomegaly (3 of 11; 27%), hepatomegaly (2 of 11; 18%) and weight loss (1 of 11; 9%). One patient had perforation of the ascending colon, and another patient had peritoneal infiltration. In one case there were cerebral seizures due to cerebral manifestation of the EBV-PTLD.
The median duration from SCT to EBV reactivation was 54 days (range 14–126) with 54 days in the adults (range 14–126) and 60 days (range 33–77) in the pediatric patients. In the majority of patients (13 of 15; 87%), the interval to EBV manifestation was <3 months; in 2 of 15 patients only, it was 3–12 months. EBV-PTLD developed with a median interval of 64 days (range 35–394) from SCT. The majority of PTLD cases (8 of 11; 73%) occurred within the first 3 months after SCT (<3 months, n=8; 3–6 months, n=1; 6–9 months, n=1; 9–12 months, n=0; >1 year, n=1). Thus, EBV-PTLD occurred in nearly all cases (10 of 11; 91%) within the first year from SCT.
Incidence of EBV reactivation/PTLD
The combined incidence of EBV-associated disorders during the study period was 26 of 854 (3.0%) (18 of 713; 2.5% in the adults and 8 of 141; 5.7% in the children). The overall incidence of EBV-PTLD was 11 of 854 (1.3%) (7 of 713; 1.0% in the adults; 4 of 141; 2.8% in children) whereas that of EBV reactivation was 15 of 854 (1.8%) with 11 of 713 (1.5%) in adult patients and 4 of 141 (2.8%) in children.
Quantification of the EBV load
Exact definition of the EBV viral load in serum by quantitative PCR was available in 15 of 28 patients (54%). In 13 of 28 cases, semiquantitative assessment was applied for the detection of EBV. Median serum EBV-DNA levels were 177 (range 100–10 400) and 250 Geq/ml (genome equivalents per ml, range 100–100 000) among the EBV reactivation and PTLD patients. EBV-DNA levels were therefore generally higher among the PTLD patients, although there was a patient with EBV reactivation who had a viral load of 10 400 Geq/ml and yet did not develop PTLD. On the other hand, there was a patient with PTLD whose viral load was only 100 Geq/ml.
Peripheral blood parameters
The median WBC was 4.5 × 109 per liter (range 2.4–16.3 × 109 liter) in the PTLD patients. The majority of patients (11 of 18 cases; 61%) had leukopenia (<4 × 109 per liter) at the time of EBV reactivation/PTLD. In particular, there was leukopenia in 5 of 9 (56%) PTLD patients. The median absolute lymphocyte count was 0.65 × 109 per liter (range 0.2–8.2 × 109 per liter) in 15 of 26 patients with available data. The median CD4+/CD8+ (CD3+ T cell) ratio was 0.3 (range 0.1–0.5) (normal range, 0.9–1.9) and thus was reduced in all nine patients where the immune status had been performed at the time of EBV manifestation.
Immunosuppression and GVHD
At the time of the EBV reactivation/PTLD, the majority of patients (21 of 26; 81%) were still on an immunosuppressive regimen (CsA: 10 of 21 patients; tacrolimus: 1 of 22; CsA/MMF: 4 of 22; CsA/high-dose steroids: 5 of 22; MMF/steroids: 1 of 22). The PTLD patients all received immunosuppression at the time of manifestation.
Acute GVHD grades I–IV occurred in 17 of 26 of the patients and grades II–IV in 14 of 26 patients. Among PTLD cases, 4 of 11 had aGVHD (grades I: 1 of 11 and II–IV: 3 of 11). Chronic GVHD was present in 4 of 16 patients who survived>100 days post-SCT (including 2 of 11 patients with PTLD).
There was a high rate of concomitant infections of bacterial, viral, fungal and parasitic origin (14 of 26; 54%) at the time of EBV reactivation/PTLD. Most frequent were central venous catheter sepsis (9 of 26; 35%) and other viral infections (9 of 26; 35%) (herpes simplex virus, HSV stomatitis: n=6; HSV pneumonia: n=2, adenovirus enteritis: n=2 and influenza A pneumonia: n=1). CMV reactivation occurred in 9 of 26 patients (35%). Fungal infections were diagnosed in 6 of 26 patients (23%) (fungal pneumonia: n=3 and fungal sepsis: n=3). Toxoplasma gondii infection was seen in 2 of 26 patients (8%).
Treatment of EBV reactivation/PTLD
At the time of EBV reactivation/PTLD, 14 of 26 (54%) received antiviral prophylaxis by acyclovir (n=8), valgancyclovir (n=2), a combination of both (n=3), or foscavir (n=1). Of the PTLD patients, 5 of 11 (45%) were on antiviral therapy.
After the diagnosis of the EBV manifestation, 8 of the 15 patients with EBV reactivation (53%) did not receive any specific treatment but still showed no increase of EBV-DNA levels. In 7 of 15 patients (47%) treatment for EBV reactivation was performed, in 6 of 8 cases by rituximab monotherapy and in 2 cases by rituximab combined with cidofovir or foscavir.
In the PTLD patients, treatment was performed in 9 of 11 patients. Two patients received rituximab monotherapy, and in seven cases rituximab was applied in combination with other approaches such as CHOP chemotherapy, virustatic treatment (cidofovir, gancyclovir, or foscavir), DLIs, or dexamethasone, as shown in detail in Table 2. Two PTLD cases remained without treatment due to the rapid and fatal courses.
Despite the therapeutic efforts, mortality was high in the patients with EBV reactivation or PTLD, as 19 of 26 (73%) died after a median of 56 days (range 2–588) following the diagnosis of EBV reactivation/PTLD. Specifically, the mortality rates were 9 of 11 (82%) in the patients with EBV-PTLD, and 10 of 15 (67%) in the patients with EBV reactivation. Thus, also in the patients with EBV reactivation only, the outcome was very unfavorable. In the PTLD patients, six of nine mortalities were directly associated with progress of the EBV-associated disorder, but three patients died due to other causes such as severe aGVHD or relapse of the underlying hematological malignancy. Mortalities in the eight patients with EBV reactivation where data were available were associated with other problems such as sepsis, extensive chronic GVHD or relapse of the hematological malignancy.
All six patients who received treatment for EBV reactivation achieved EBV-DNA negativity. Among the 9 of 11 PTLD patients who received specific treatment, 3 of 9 (33%) achieved complete lymphoma remission and 1 patient achieved PR with regression of lymphadenopathy and serum EBV-DNA negativity, but died from relapse of AML complicated by pneumonia and sepsis. Five of nine patients with PTLD (56%) were refractory to therapy and died after a few days.
Irrespective of advanced schedules of surveillance, prevention and control of infectious disorders in the post transplant period, the problem of EBV-associated disorders remains unsolved. Intending to further characterize the problem of EBV-associated disorders in the post transplantation setting, we here performed retrospective analysis of 26 patients with EBV reactivation or EBV-associated PTLD who received SCT in recent years in our center.
First, the incidence of post transplant EBV reactivations/PTLD has been observed to vary considerably in different studies. The overall frequencies of EBV reactivation and PTLD in this study were 3.3 and 1.4%, respectively. Thus, a low incidence was observed, although most patients received ATG within the conditioning regimen. This was in contrast to the suggestion of Van Esser et al.13 that there might be a strong association of EBV manifestation with the use of ATG. Also, the frequency in this study was lower than the 7.4% reported in the study of Juvonen et al.4 where many patients received ATG. Therefore, other parameters probably influence the development of EBV-PTLD in the post transplant period as well. The incidence of EBV reactivation/PTLD in the pediatric patients (5.7%) was similar with other reports ranging from 5 to 12%.19, 20
Searching for associations between EBV-DNA loads and the clinical manifestation, PTLD patients had a higher median EBV-DNA level of 250 Geq/ml (range 100–100 000) when compared to patients with EBV reactivation who had a median level of 177 Geq/ml (range 100–10 400). It was interesting to note that one patient with EBV reactivation whose EBV-DNA level was>10 000 Geq/ml did not develop PTLD, whereas another patient with PTLD showed only 100 Geq/ml EBV-DNA in the serum but developed colon perforation due to intestinal lymphoma infiltration. These cases support previous observations that some patients with PTLD have low EBV-DNA levels just like patients with only EBV reactivation who never proceed to PTLD.12
It further should be discussed, whether certain thresholds of EBV-DNA levels can be interpreted as a signal for the start of pre-emptive treatment to prevent the progression of reactivation to PTLD. Van Esser et al.13 used rituximab as pre-emptive therapy when the EBV-DNA level was⩾1000 Geq/ml which was sufficient to achieve complete viral clearance in nearly all cases. Others also demonstrated that an EBV DNA load⩾1000 Geq/ml is a high risk for transformation to PTLD.13, 14, 15, 21 However, this strategy—simply based on the EBV-DNA load—may result in unnecessary treatment in some patients.13, 15 Therefore, additional assessment of the EBV-specific T-cell reconstitution during the reactivation process might define the patients at risk for EBV-PTLD more precisely.15, 22, 23 As the cumulative EBV-specific CD8+ T-cell repertoire was observed to increase significantly during the EBV reactivation process, a prospective study was performed limiting the application of rituximab to patients with poor T-cell recovery which was indeed sufficient for control of EBV reactivation and prevention of PTLD.15
The assessment of risk factors for EBV-associated complications showed that the majority of patients in this study (81%) were on an immunosuppressive regimen at the time of EBV manifestation, and a high proportion (65%) had acute or chronic GVHD. This suggests an association between the intensity of immunosuppression, the reduced immunity in patients with GVHD and the development of EBV reactivation/PTLD. In the study by Juvonen et al.4 all PTLD patients were reported to have had aGVHD. The high rates of leukopenia, lymphopenia and reduced CD4+/8+ ratios and the high rate of concomitant bacterial, viral and fungal infections of 54% at the time of EBV manifestation being observed in this study also suggested poor immune reconstitution in the affected patients.
Another open question is the definition of the interval when patients are at most risk for the development of EBV-associated disorders after SCT. In this study, median intervals were 54 days (range 14–126) from SCT to EBV reactivation and 64 days (range 35–394) to the manifestation of PTLD. A late onset of EBV-PTLD was seen in only 9% of patients, which was in contrast to a the results of Martin-Gomez et al.5 who saw a late onset of EBV-PTLD after the first year in the majority (74%) of patients. Thus, it remains open, whether monitoring of EBV on a weekly basis24 should be continued more than 1 year after SCT.
Various strategies such as DLIs, virustatic compounds such as foscavir or cidofovir, cytotoxic therapy, for example CHOP, or anti-CD20 treatment were performed in the management of EBV reactivations and PTLD. Others included EBV-specific cytotoxic T cells and proliferation signal inhibitors such as sirolimus.3, 4, 5, 10, 11, 12, 13, 25, 26, 27 These therapeutic concepts were either performed as single approaches or in variable combinations with variable doses and numbers of treatment cycles, and mortality rates irrespective of these multimodal approaches are high in patients with EBV-associated PTLD in this as in previous studies.1, 2 Therefore, prospective multicenter studies should be initiated aiming to develop standardized surveillance and treatment strategies to improve management of EBV-associated disorders in the post transplant period.
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The authors appreciate the dedicated care of patients by all members of the Transplantation Team. Dr S Ocheni is grateful to Professor A R Zander and Professor N Kroeger for a Clinical Fellowship at the Stem Cell Transplantation Department of the University of Hamburg, Germany.
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Ocheni, S., Kroeger, N., Zabelina, T. et al. EBV reactivation and post transplant lymphoproliferative disorders following allogeneic SCT. Bone Marrow Transplant 42, 181–186 (2008). https://doi.org/10.1038/bmt.2008.150
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