Epstein-Barr Virus (EBV) Reactivation, Its Treatment with Rituximab and Their Impact on Relapse after Allogeneic Hematopoietic Stem Cell Transplantation for Hematological Malignancies

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3695-3695 ◽  
Author(s):  
Mauricette Michallet ◽  
Mohamad Sobh ◽  
Florence Ranchon ◽  
Sandrine Leroy ◽  
Fiorenza Barraco ◽  
...  
Keyword(s):  
B Cells ◽  
Cumulative Incidence ◽  
Myeloid Leukemia ◽  
Hematological Malignancies ◽  
Advisory Committees ◽  
Hematopoietic Stem ◽  
Barr Virus ◽  
Ebv Reactivation ◽  
Ebv Dna ◽  
Epstein Barr

Abstract Background: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative approach for a wide range of hematologic malignancies. However, the period of prolonged immunodeficiency after this procedure results in significant morbidity and mortality from infectious complications. Epstein-Barr virus (EBV) is a latent γ-herpes virus with B lymphocyte-specific tropism that infects more than 90% of healthy individuals. Following allo-HSCT, EBV reactivation and EBV-related proliferations may be associated with a spectrum of clinical presentations, going from fever to lymphoproliferative diseases (LPD), which arise as a consequence of an outgrowth of B cells latently infected with EBV in the setting of loss or suppression of normal cytotoxic T-cell surveillance. Reduction in immunosuppression and/or pre-emptive therapy with rituximab are strategies nowadays employed to prevent or to treat EBV-associated LPD, which have led to a significant improvement in patient outcome. While the role of T cells and NK cells in graft-versus-leukemia (GVL) immune responses has been established, recent studies have shown a potential contribution of B cells on GVL responses. In this context, the impact of the use of monoclonal antibodies targeting B cells lines on disease control has not been evaluated yet. The aim of this study is to evaluate the incidence of EBV reactivation in patients with hematological malignancies after allo-HSCT, the use of rituximab for its treatment and its impact on the transplantation outcomes. Patients and methods: We evaluated 359 consecutive patients with hematological malignancies who received allo-HSCT and were followed in our center between January 2008 and June 2015; there were 218 (61%) males and 141 (39%) females with a median age of 48 years (range: 18-70), 182 (51%) had acute myeloid leukemia, 44 (12%) multiple myeloma, 34 (9%) myelodysplastic syndrome, 30 (8%) Non-Hodgkin lymphoma, 7 (2%) chronic lymphocytic leukemia, 21 (6%) myeloproliferative syndrome, 14 (4%) Hodgkin disease, 13 (4%) chronic myeloid leukemia and 14 (4%) aplastic anemia. At transplantation, 227 (63%) patients were in complete response (CR) or chronic phase (CP) and 132 (37%) were in less than CR or CP. For conditioning regimen, 171 (48%) were myeloablative and 188 (52%) were reduced intensity. EBV DNA levels in blood were detected by quantitative real-time polymerase chain reaction (RQ-PCR) after weekly monitoring up to 3 months after allo-HSCT. EBV-DNA was considered positive when the copies exceeded 1000 copies/ml. EBV therapeutic intervention, firstly concerned gradual reduction of the doses of immunosuppressive drugs, and then rituximab infusion (375 mg/m², four injections weekly) was administered when the copies exceeded 10 000 copies/ml. Results: Among 359 patients, 222 patients had EBV reactivation after a median time of 1.3 months (0.7-2.5) after allo-HSCT with a cumulative incidence of 48 % (47-50) at 3 months. Among the 222 patients with EBV reactivation, only 35 (15.7%) needed treatment with rituximab. Rituximab was introduced after a median time of 55 days after transplantation with a median number of 5 infusions and a median dose of 2025 mg/m². EBV treatment was successful in all patients, none progressed to LPD. The cumulative incidence of relapse at one and two years for the whole population was 27% (26-28) and 34% (33-35) respectively and the cumulative incidence of transplant-related mortality (TRM) was 22% (21-23) and 25% (24-26) respectively. The multivariate analysis taking into account the type of disease, the type of conditioning, the use of ATG, the disease status at transplantation, the presence of GVHD and the EBV reactivation with/without rituximab, showed that the presence of EBV reactivation was associated with a significant lower relapse rate, HR= 0.52 [0.35-1], p=0.05. The use of rituximab did not compromise the GVL effect and thus had not impact on relapse or overall survival. Conclusion: We showed a positive impact of EBV reactivation on relapse incidence which could be explained as a stimulation of both function and amplification of NK compartment. The strict monitoring of the viral load and therapeutic intervention using rituximab enable a full viral control without any progression into LPD and without any compromise on GVL effect. Figure 1. Figure 1. Disclosures Michallet: Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Astellas Pharma: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria. Nicolini:Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals How I treat EBV lymphoproliferation

Blood ◽  
2009 ◽  
Vol 114 (19) ◽  
pp. 4002-4008 ◽  
Author(s):  
Helen E. Heslop
Keyword(s):  
B Cells ◽  
Cytotoxic T Lymphocyte ◽  
Cytotoxic T Cells ◽  
Treatment Options ◽  
Solid Organ Transplantation ◽  
Solid Organ ◽  
Hematopoietic Stem ◽  
Serial Measurement ◽  
Barr Virus ◽  
Epstein Barr

Abstract Epstein-Barr virus (EBV)–associated B-cell lymphoproliferation is a life-threatening complication after hematopoietic stem cell or solid organ transplantation resulting from outgrowth of EBV-infected B cells that would normally be controlled by EBV-cytotoxic T cells. During the past decade, early detection strategies, such as serial measurement of EBV-DNA load in peripheral blood samples, have helped to identify high-risk patients and to diagnose early lymphoproliferation. Treatment options include manipulation of the balance between outgrowing EBV-infected B cells and the EBV cytotoxic T lymphocyte response and targeting the B cells with monoclonal antibodies or chemotherapy. Major challenges remain for defining indications for preemptive therapies and integrating novel and conventional therapies.

scholarly journals Points of Recombination in Epstein-Barr Virus (EBV) Strain P3HR-1-Derived Heterogeneous DNA as Indexes to EBV DNA Recombinogenic Events In Vivo

2008 ◽  
Vol 82 (23) ◽  
pp. 11516-11525 ◽  
Author(s):  
Kazufumi Ikuta ◽  
Shamala K. Srinivas ◽  
Tim Schacker ◽  
Jun-ichi Miyagi ◽  
Rona S. Scott ◽  
...  
Keyword(s):  
Epstein Barr Virus ◽  
Lymphoid Cells ◽  
Defective Interfering Particles ◽  
Barr Virus ◽  
Ebv Reactivation ◽  
Pcr Products ◽  
Ebv Dna ◽  
Epstein Barr

ABSTRACT Deletions and rearrangements in the genome of Epstein-Barr virus (EBV) strain P3HR-1 generate subgenomic infectious particles that, unlike defective interfering particles in other viral systems, enhance rather than restrict EBV replication in vitro. Reports of comparable heterogeneous (het) DNA in EBV-linked human diseases, based on detection of an abnormal juxtaposition of EBV DNA fragments BamHI W and BamHI Z that disrupts viral latency, prompted us to determine at the nucleotide level all remaining recombination joints formed by the four constituent segments of P3HR-1-derived het DNA. Guided by endonuclease restriction maps, we chose PCR primer pairs that approximated and framed junctions creating the unique BamHI M/B1 and E/S fusion fragments. Sequencing of PCR products revealed points of recombination that lacked regions of extensive homology between constituent fragments. Identical recombination junctions were detected by PCR in EBV-positive salivary samples from human immunodeficiency virus-infected donors, although the W/Z rearrangement that induces EBV reactivation was frequently found in the absence of the other two. In vitro infection of lymphoid cells similarly indicated that not all three het DNA rearrangements need to reside on a composite molecule. These results connote a precision in the recombination process that dictates both composition and regulation of gene segments altered by genomic rearrangement. Moreover, the apparent frequency of het DNA at sites of EBV replication in vivo is consistent with a likely contribution to the pathogenesis of EBV reactivation.

scholarly journals A Delayed Innate T Cell Reconstitution Is Associated with Epstein-Barr Virus Reactivation after Haploidentical Hematopoietic Stem Cell Transplantation Using Anti-Thymoglobulin and High-Dose Post-Transplant Cyclophosphamide

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3398-3398
Author(s):  
Nicolas Stocker ◽  
Agathe Farge ◽  
Laure Ricard ◽  
Vincent Jachiet ◽  
Clemence Mediavilla ◽  
...  
Keyword(s):  
T Cells ◽  
Progression Free Survival ◽  
High Dose ◽  
Unrelated Donor ◽  
Hematopoietic Stem ◽  
Mait Cells ◽  
Barr Virus ◽  
Ebv Reactivation ◽  
Innate T Cells ◽  
Epstein Barr

Abstract Background: Allogeneic hematopoietic stem cell transplantation (allo-HCT) using a haploidentical donor (haplo-HCT) using post-transplant high-dose cyclophosphamide (PTCy) is increasingly used for patients lacking a matched related or unrelated donor. We recently noticed a relatively high incidence of infectious complications, especially Epstein-Barr virus (EBV) reactivation after haplo-HCT. However, the mechanisms underlying the increased incidence of this complication in the haplo-HCT setting are unknown. We hypothesized that the use of PTCy may be associated with a deficit in innate-like effector T cells essential for preventing EBV reactivation.This study aimed to analyze immune reconstitution following haplo-HCT using peripheral blood stem cells (PBSC) grafts and to evaluate the correlations with EBV reactivation and outcomes. Patients and Methods: One hundred and twenty-three consecutive patients who underwent allo-HCT for hematological malignancies between 2013 and 2016 were included in this single-center retrospective study. All patients received G-CSF mobilized PBSC grafts and ATG 2.5-5 mg/Kg total dose. All patients received a combination of cyclosporine A and mycophenolate mofetil for GvHD prophylaxis, except for patients with a matched related donor (MRD) who received cyclosporine A alone and patients with an haploidentical donor who received PTCy (50mg/kg/d at d3+/-d5). α/β T cells (CD3+, CD4+ and CD8+), γ/δ T cells (pan γ/δ and Vδ2+), mucosal-associated T cells wich express a highly restricted TCR comprising a semi-variant Vα7.2-Jα33 (MAIT), invariant NK T cells, NK cells, B cells, Tregs, monocytes subsets and dendritic cells (myeloid DC, plasmacytoid DC and Slan-DC) were analyzed by multi-color flow cytometry at months (M) 1, 3, 6 and 12 following allo-HCT. Clinical data [acute GvHD (aGvHD), relapse incidence, chronic GvHD (cGvHD), viral reactivations, bacterial and fungal infections, non-relapse mortality (NRM), progression-free survival (PFS), refined GvHD-free and progression-free survival (GPFS), overall survival (OS)] were assessed together with sequential quantitative evaluation of immune subsets. Results: Median age was 55 (range, 17-70) years, with 32 male patients (26%) receiving a graft from a female donor. Diagnoses were myeloid malignancies (66%) or lymphoid malignancies (34%). Thirty-three patients (27%) received a graft from a MRD, 65 from an unrelated donor (MUD, 53%), and 25 from a haplo-identical donor (20%). Thirty patients (24%) with refractory disease received a sequential conditioning regimen while the remaining (n=93, 76%) received a RIC/RTC regimen based on fludarabine, busulfan +/- thiotepa. At d180, the cumulative incidences (CIs) of grade II-IV and grade III-IV aGvHD were 34% and 5%, respectively. The 2 years CIs of cGvHD, extensive cGvHD and relapse were 23%, 8% and 17%, respectively. At 2 years, NRM was 7%, PFS was 77%, GPFS was 66% and OS was 83%. The rate of EBV reactivation was significantly increased in haplo-HCT recipients as compared to fully-matched donor recipients (respectively, 68% versus 26%, P< .001). At one month after allo-HCT, the median counts of all immune cells subsets (except monocytes) was significantly lower in haplo-HCT recipients as compared to MRD or MUD recipients. At 3 months, α/β T cells, iNK T cells, NK cells, B cells, Tregs and Slan-DC reached similar median counts in haplo-HCT recipients as compared to MRD or MUD recipients. In contrast, Vδ2+ T cells and MAIT cells median counts remained significantly lower at 3, 6 and 12 months in haplo-HCT recipients compared to MRD or MUD recipients (at M1, M3, M6, M12, the median Vδ2+ T cells counts were 0.05/µL, 0.24/µL, 1.38/µL and 2.97/µL, and MAIT cells were 0.07/µL, 0.70/µL, 1.00/µL and 1.21/µL, respectively). Lower Vδ2+ T-cells and MAIT cells counts at one month was associated with a significantly increased CI of EBV reactivation (respectively, P=.04 and P<.0001) in landmark study. Conclusion: Immunological reconstitution of innate T cells is significantly delayed after haplo-HCT and low-dose ATG and PTCy. This prolonged deficiency is associated with an increased risk of EBV reactivation. Development of new strategies for innate-T cells expansion are necessary after haplo-HCT. Disclosures Mohty: MaaT Pharma: Consultancy, Honoraria.

scholarly journals Methylation of the Epstein-Barr Virus Genome in Normal Lymphocytes

Blood ◽  
1997 ◽  
Vol 90 (11) ◽  
pp. 4480-4484 ◽  
Author(s):  
Keith D. Robertson ◽  
Richard F. Ambinder
Keyword(s):  
B Cells ◽  
Epstein Barr Virus ◽  
Defense Mechanism ◽  
Immune Surveillance ◽  
Virus Genome ◽  
Barr Virus ◽  
The Face ◽  
Ebv Dna ◽  
Epstein Barr

Abstract Epstein-Barr virus (EBV) latent infection in B cells persists over years or decades despite a sustained cytotoxic immune response to viral antigens. We present data that methylated EBV DNA can be detected in the normal lymphocytes of healthy volunteers. Whereas methylation of foreign DNA has been recognized as a potential cellular defense mechanism, methylation of EBV DNA may be an essential part of the virus life cycle in vivo, explaining the persistence of virus-infected B cells in the face of immune surveillance. Methylation of the C promoter helps to prevent expression of the immunodominant antigens expressed from this promoter. First recognized in tumors, methylation-associated evasion of immune surveillance is not an aberration restricted to tumor tissue but is detected in normal EBV-infected lymphocytes. Methylation of the viral genome in latency also provides an explanation for the CpG suppression associated with EBV but not other large DNA viruses.

Epstein-Barr Virus Infection In Recipient Of Allogeneic Hematopoietic Stem Cell Transplantation: The Role Of Cytomegalovirus

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4555-4555
Author(s):  
Qifa Liu ◽  
Ren Lin ◽  
Can Liu ◽  
Meiqing Wu ◽  
Li Xuan ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Research Funding ◽  
Epstein Barr Virus ◽  
Hematopoietic Stem ◽  
Barr Virus ◽  
Ebv Infection ◽  
Associated Diseases ◽  
Ebv Dna ◽  
Epstein Barr

Background Epstein-Barr virus (EBV) infection is a common complication in recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT), leading to fatal post-transplant lymphoproliferative disorders (PTLD) and other EBV-associated diseases. A few studies suggested that cytomegalovirus (CMV) might play a role in PTLD. In this study, the effect of CMV on EBV DNA-emia and EBV-associated diseases was evaluated in the recipients of allo-HSCT. Methods Three hundred and fifty-two patients undergoing allo-HSCT were enrolled in this prospective study between July 2008 and June 2013. The EBV-DNA and CMV-DNA levels in blood and secretion were monitored by quantitative real-time polymerase chain reaction (RQ-PCR) before and in different time points after transplantation. EBV and CMV DNA-emia were diagnosed when EBV-DNA or CMV-DNA in the blood was positive twice consecutively. Results During the follow-up period, 99 patients (28.1%) developed EBV DNA-emia and 41 (11.6%) developed EBV-associated diseases including 27 EBV-associated PTLD and 14 other EBV-associated diseases. One hundred and fifty-nine patients (45.2%) developed CMV DNA-emia and 10 (2.8%) developed CMV-associated diseases. Of the 99 patients who developed EBV DNA-emia, 56 had CMV DNA-emia before EBV DNA-emia, and the median time from occurrence of CMV DNA-emia to EBV DNA-emia and EBV-associated diseases were 15 (range, 0-269) days and 26 (range, 0-255) days, respectively. Six patients developed co-existing CMV DNA-emia at the time of EBV-associated diseases diagnosed. DNA-emia before EBV infection had positive correlation with EBV DNA-emia (r=0.14, p=0.007) and EBV-associated diseases (r=0.15, p=0.005), but both correlation coefficients were weak. There was a strong positive correlation between EBV DNA-emia and EBV-associated diseases (r=0.56, p<0.001). The patients with CMV DNA-emia had a higher risk for developing EBV infection than those without (OR 2.279, 95% confidence interval [CI] 1.420-3.657, p=0.001). After EBV infection occurred, 15 patients developed CMV DNA-emia, including 4 developed CMV-associated diseases, at a median time of 33 days (range, 12-50 days). EBV infection was not related to CMV DNA-emia (p=0.87) or CMV associated diseases (p=0.27) occurring after EBV infection. Conclusion The results suggest that CMV may play a contributory role in the development of EBV DNA-emia and EBV-associated diseases. Disclosures: Liu: This work was supported by the National High Technology Research and Development Program of China (863 Program) (No. 2011AA020105), the National Public Health Grand Research Foundation (Grant No. 201202017).: Research Funding; This work was also supported by National Natural Science Foundation of China (Grant No.81000231, No.30971300, No.81270647), the Science and Technology Project of Guangdong Province of China (Grant No.2009A030200007).: Research Funding; This work was also supported by the Science and Technology Program of Guangzhou of China (11A72121174).: Research Funding.

scholarly journals Prevention of Epstein-Barr virus–lymphoproliferative disease by molecular monitoring and preemptive rituximab in high-risk patients after allogeneic stem cell transplantation

Blood ◽  
2002 ◽  
Vol 99 (12) ◽  
pp. 4364-4369 ◽  
Author(s):  
Joost W. J. van Esser ◽  
Hubert G. M. Niesters ◽  
Bronno van der Holt ◽  
Ellen Meijer ◽  
Albert D. M. E. Osterhaus ◽  
...  
Keyword(s):  
High Risk ◽  
Epstein Barr Virus ◽  
Lymphoproliferative Disease ◽  
Viral Reactivation ◽  
Preemptive Therapy ◽  
Barr Virus ◽  
Ebv Reactivation ◽  
Risk Patients ◽  
Ebv Dna ◽  
Epstein Barr

Recipients of a partially T-cell–depleted (TCD) allogeneic stem cell transplantation (allo-SCT) developing reactivation of Epstein-Barr virus (EBV) with quantified viral DNA levels exceeding 1000 genome equivalents/milliliter (geq/mL) are at high risk for EBV–lymphoproliferative disease (EBV-LPD). We studied whether preemptive therapy with rituximab prevents EBV-LPD, LPD-mortality, and abrogates viral reactivation in high-risk patients. We monitored 49 recipients of a TCD allo-SCT weekly for EBV reactivation by quantitative real-time polymerase chain reaction (PCR). Preemptive therapy by a single infusion of rituximab was given to patients with viral reactivation more than or equal to 1000 geq/mL. Results were compared with an historical control group of patients retrospectively monitored for EBV reactivation at similar intervals. There were 17 prospectively monitored patients who showed EBV reactivation more than or equal to 1000 geq/mL and 15 received preemptive therapy. Median time to preemptive therapy was 113 days (range, 41-202 days) after SCT. There were 14 patients who showed complete response (CR) as characterized by prevention of EBV-LPD and complete clearance of EBV-DNA from plasma, which was achieved after a median number of 8 days (range, 1-46 days). One patient progressed to EBV-LPD despite pre-emptive therapy, but obtained CR after 2 infusions of rituximab and donor lymphocyte infusion. There were 2 patients who had already developed EBV-LPD prior to preemptive rituximab, but obtained CR following 2 rituximab infusions. Comparison of this prospectively followed series to our historical cohort with the same high-risk profile showed a reduction of EBV-LPD incidence (18% ± 9% versus 49% ± 11%, respectively) and a complete abrogation of LPD-mortality (0% versus 26% ± 10%, respectively) (P = .04) at 6 months from EBV-DNA more than or equal to 1000 geq/mL. Frequent quantitative monitoring of EBV reactivation and preemptive therapy by rituximab improves outcome in patients at high risk of EBV-LPD.

Influence of the 1st International WHO EBV Standard on quantitation of Epstein-Barr virus viral load in serum samples

2019 ◽  
Vol 54 (2) ◽  
pp. 85-90
Author(s):  
Maciej Przybylski ◽  
Anna Majewska ◽  
Natalia Żeber-Lubecka ◽  
Grażyna Młynarczyk ◽  
Tomasz Dzieciątkowski
Keyword(s):  
Epstein Barr Virus ◽  
Positive Impact ◽  
Serum Samples ◽  
Hematopoietic Stem ◽  
Conversion Factors ◽  
Barr Virus ◽  
Before And After ◽  
Ebv Dna ◽  
Epstein Barr ◽  
The Impact

Objectives: The aim of this study was to evaluate the impact of normalization with 1<sup>st</sup> International WHO Standard for Epstein-Barr Virus (EBV) on EBV DNA quantitation in 90 clinical serum samples obtained from hematopoietic stem cells transplant recipients. Methods: EBV DNA loads (EDLs) obtained with the use of six different commercially available and in-house developed assays, including various automated DNA extraction systems, real-time PCR tests and cyclers were compared, both before and after recalculation with conversion factors obtained with 1st International WHO Standard for Epstein-Barr Virus Results: None of six methods was able to detect EBV DNA in all 80 serum samples identified previously as positive but the most effective method turned out to be combination of MagnaPure, LC2.0 and EBV QK (sensitivity 90%). Conversion factors for compared assays, obtained with the WHO standards ranged from 0.998 (MagnaPure/LC2.0/EBV QK) to 1.138 (MagnaPure/LC2.0/<I>In house</I>). In two out of four comparisons, differences in the average EDLs, initially significant, have changed to statistically not significant after conversion to IU/mL. Conclusions: Positive impact of EDLs standardization was shown, resulting in lower discrepancies between average values obtained with various methods. Method-to-method variability was lower for samples with a higher EDLs (>3.5 log), regardless the units used. Results showed the advantage of certain commercial methods over “in-house” method.

Molecular Monitoring and Stepwise Preemptive Therapy to Prevent Epstein-Barr Virus-Associated Diseases After Allogeneic Hematopoietic Stem Cell Transplantation.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3067-3067
Author(s):  
Li Xuan ◽  
Ke Zhao ◽  
Fen Huang ◽  
Meiqing Wu ◽  
Xiao Zhai ◽  
...  
Keyword(s):  
Risk Factors ◽  
Epstein Barr Virus ◽  
Antiviral Agents ◽  
Preemptive Therapy ◽  
Hematopoietic Stem ◽  
Barr Virus ◽  
Associated Diseases ◽  
Ebv Dna ◽  
Epstein Barr ◽  
Ebv Viremia

Abstract Abstract 3067 Background: Epstein-Barr virus (EBV)-associated diseases progress rapidly and are severe complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Despite various therapeutic options being developed, the mortality of EBV-associated disease is still high. As the EBV-DNA loads of blood are associated with the occurrence of EBV-associated disease, we developed a stepwise preemptive therapy (administration of antiviral agents and reduction of immunosuppression [IS] followed by rituximab treatment) based on quantitative real-time polymerase chain reaction (RQ-PCR) monitoring EBV-DNA levels. Methods: The blood EBV-DNA levels were regularly monitored by RQ-PCR in 192 recipients of allo-HSCT. The stepwise preemptive therapy was administered in patients experiencing blood EBV-DNA positive (more than 500 copies/ml) twice consecutively. Administration of antiviral agents and reduction of IS were first taken. If EBV-DNA was continuously positive four times with a rising trend, rituximab was administered weekly until EBV-DNA was negative or for a total of 4 times. The patients who were diagnosed as EBV-associated diseases or appeared the signs and symptoms of EBV-associated diseases within three days after preemptive therapy were withdrawn from the study of preemptive therapy. Results: Sixty patients developed EBV viremia and 31 developed EBV-associated diseases, including 19 EBV-associated post-transplant lymphoproliferative diseases (PTLD) and 12 EBV-associated other diseases (7 EBV-associated fever, 1 encephalitis, 1 myelitis, 1 encephalitis with lung involvement, 1 encephalitis with lung and liver involvement and 1 pneumonia). The median time to onset of EBV viremia and EBV-associated diseases was 51 days (range, 22–368 days) and 65 days (range, 22–289 days) post-transplantation, respectively. The 3-year cumulative incidence of EBV-viremia and EBV-associated diseases was 34.0% ± 3.7% and 18.1% ± 3.0%. The 3-year cumulative incidence of EBV-associated diseases rose steeply with increasing number of risk factors: 2.7% ± 1.9%, 16.9% ± 11.0%, 36.7% ± 7.8% and 37.6% ± 9.0% for patients with 0, 1, 2, and 3 major risk factors (antithymocyte globulin, unrelated donor and HLA-mismatched, as none of the grafts were T-cell-depleted), respectively. The EBV-DNA levels of blood exceeded the threshold for 0 to 17 (median 7) days before the clinical manifestations of EBV-associated diseases emerged. Fifty-five patients received the first-step preemptive therapy and 12 cases followed by rituximab preemptive treatment. Nineteen (34.5%) cases became EBV-DNA negative, and 36 showed no response including 24 progressing to EBV-associated diseases during the first-step preemptive therapy. The effective rates of antiviral agents and antiviral agents plus reduction of IS were 11.1% and 45.9%, respectively (P=0.011). Of the 12 patients undergoing rituximab preemptive therapy, 11 (91.7%) cases achieved complete responses (CR) and one progressed to PTLD. The effective rates of preemptive therapy were 100%, 75%, 48% and 50% for patients with 0, 1, 2, or 3 major risk factors, respectively. Twenty-three (88.5%) of the 26 cases obtained CR after rituximab-based treatments; one case without use of rituximab and four who gave up treatment all died of EBV-associated diseases. Of the 23 cases with CR, 17 survived and 6 died with a median follow up of 320 days (range, 62 to 1070 days) after the onset of EBV-associated diseases. Conclusions: The stepwise preemptive therapy has some effect on prevention of EBV-associated diseases, but more frequent monitoring of blood EBV-DNA levels and earlier preemptive rituximab should be advocated in patients at high risk of EBV-associated diseases. Disclosures: No relevant conflicts of interest to declare.

Effect of Antithymocyte Globulin Dosage for Prophylactic Gvhd On Epstein-Barr Virus Reactivation and Diseases in Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4486-4486
Author(s):  
Guo-pan Yu ◽  
Qifa Liu ◽  
Jing SUN ◽  
Li Xuan ◽  
Meiqing Wu ◽  
...  
Keyword(s):  
Dose Group ◽  
Low Dose ◽  
High Dose Group ◽  
High Dose ◽  
Hematopoietic Stem ◽  
Barr Virus ◽  
Ebv Reactivation ◽  
Epstein Barr ◽  
High Degree ◽  
Medium Dose

Abstract Abstract 4486 Background: Antithymocyte globulin (ATG) is one of the main risk factors for Epstein-Barr virus (EBV) reactivation and disease in allogeneic hematopoietic stem cell transplantation (allo-HSCT), however, whether there is a correlation between ATG dose and EBV reactivation is unsure. Aim of this single-center prospective study is to explore the relationship between ATG dose and EBV reactivation in allo-HSCT. Methods: Ninety-nine patients with hematologic malignancies underwent allo-HSCT and administration of ATG for graft versus host disease (GVHD) prophylaxis were enrolled in this study in Nanfang hospital from February 2008 to February 2012. Sixty-one patients were unrelated donor transplants, thirty-eight were HLA-mismatched related donor transplants. GVHD prophylactic regimen was cyclosporine A+Methotrexate+ATG. According to donors' HLA matching, we chose three dosage groups of prophylactic ATG: low dose group with ATG dose of 5.0∼6.0mg/kg (n=28), medium dose group with ATG dose of 7.0∼8.0mg/kg (n=55), and high dose group with ATG doses of ≥10mg/kg (n=16). The levels EBV-DNA in plasma were regularly monitored by quantitative real-time polymerase chain reaction (RQ-PCR). Results: With a median follow-up of 21 (range, 1–50) months post allo-HSCT, the cumulative incidence of EBV viremia and EBV-associated diseases was 17.6% (5/28) and 17.6% (5/28) in low dose group, respectively, with 32.7% (18/55) and 29.1% (16/55) in medium dose group, respectively, with 50.0% (8/16) and 31.3% (5/16) in high dose group, respectively. There were statistical significances of the incidence (χ2□□9.555, P=0.008). Logistic regression models showed that ATG prophylaxis was one of the main risk factors for EBV infection (RR=16.728, P=0.000) while bivariate correlation analysis presented that the incidence of EBV reactivation was positively correlated with ATG prophylaxis dosage (rpearman = 0.452, P = 0.000). The cumulative incidence of high degree (II∼IV°) aGVHD was 35.7% (10/28) in low dose group, with 39.6% (21/53) in total and 50.0% (6/12) in relapsed leukemia with HLA-mismatched related transplantation in medium dose group, with 68.8% (11/16) in high dose group. There were not statistical significances of the incidence (χ2□□6.971, P=0.137). Conclusion: EBV reactivation might be positively correlated with ATG prophylaxis dosage. According to donors' HLA matching, reducing ATG prophylaxis dose appropriately could prevent EBV reactivation in allo-HSCT without increasing high degree aGVHD. Disclosures: No relevant conflicts of interest to declare.

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