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.

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.

scholarly journals How I treat T-cell chronic active Epstein-Barr virus disease

Blood ◽  
2018 ◽  
Vol 131 (26) ◽  
pp. 2899-2905 ◽  
Author(s):  
Catherine M. Bollard ◽  
Jeffrey I. Cohen
Keyword(s):  
T Cells ◽  
T Cell ◽  
Epstein Barr Virus ◽  
Histone Deacetylase Inhibitors ◽  
Virus Disease ◽  
High Dose ◽  
Hematopoietic Stem ◽  
Curative Therapy ◽  
Barr Virus ◽  
Epstein Barr

Abstract T-cell chronic active Epstein-Barr virus (CAEBV) is a rare disease in which EBV is present predominantly in T cells that infiltrate the tissues; patients have high levels of EBV in the blood. If untreated, patients often develop liver failure, hemophagocytic lymphohistiocytosis, coronary artery aneurysms, EBV infiltrating T cells impairing organ function, or T-cell lymphomas refractory to treatment. At present, hematopoietic stem-cell transplantation is the only curative therapy, and it is critical to make a proper diagnosis and initiate transplantation before the disease progresses to an irreversible stage. Specific medications such as high-dose systemic corticosteroids or ganciclovir combined with either histone deacetylase inhibitors or bortezomib may temporarily reduce systemic toxicity associated with T-cell CAEBV and allow the patient time to receive a transplant. Relapses of the disease after transplantation have also occurred, and the use of donor-derived virus-specific T cells may help to treat these relapses.

scholarly journals Nivolumab treatment of relapsed/refractory Epstein-Barr virus–associated hemophagocytic lymphohistiocytosis in adults

Blood ◽  
2020 ◽  
Vol 135 (11) ◽  
pp. 826-833 ◽  
Author(s):  
Pengpeng Liu ◽  
Xiangyu Pan ◽  
Chong Chen ◽  
Ting Niu ◽  
Xiao Shuai ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Hemophagocytic Lymphohistiocytosis ◽  
Epstein Barr Virus ◽  
Sequencing Analysis ◽  
Hematopoietic Stem ◽  
Barr Virus ◽  
Life Threatening ◽  
Programmed Death Protein 1 ◽  
Epstein Barr

Abstract Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis (EBV-HLH) is a life-threatening hyperinflammatory syndrome triggered by EBV infection. It often becomes relapsed or refractory (r/r), given that etoposide-based regimens cannot effectively clear the virus. r/r EBV-HLH is invariably lethal in adults without allogeneic hematopoietic stem cell transplantation. Here, we performed a retrospective analysis of 7 r/r EBV-HLH patients who were treated with nivolumab on a compassionate-use basis at West China Hospital. All 7 patients tolerated the treatment and 6 responded to it. Five of them achieved and remained in clinical complete remission with a median follow-up of 16 months (range, 11.4-18.9 months). Importantly, both plasma and cellular EBV-DNAs were completely eradicated in 4 patients. Single-cell RNA-sequencing analysis showed that HLH syndrome was associated with hyperactive monocytes/macrophages and ineffective CD8 T cells with a defective activation program. Nivolumab treatment expanded programmed death protein-1–positive T cells and restored the expression of HLH-associated degranulation and costimulatory genes in CD8 T cells. Our data suggest that nivolumab, as a monotherapy, provides a potential cure for r/r EBV-HLH, most likely by restoring a defective anti-EBV response.

scholarly journals 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 ◽  
2003 ◽  
Vol 101 (11) ◽  
pp. 4290-4297 ◽  
Author(s):  
Pauline Meij ◽  
Joost W. J. van Esser ◽  
Hubert G. M. Niesters ◽  
Debbie van Baarle ◽  
Frank Miedema ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
High Risk ◽  
Cd8 T Cells ◽  
Lymphoproliferative Disease ◽  
Barr Virus ◽  
Ebv Reactivation ◽  
Epstein Barr ◽  
High Level ◽  
Very High

Abstract Epstein-Barr virus (EBV)—specific cytotoxic T lymphocytes are considered pivotal to prevent lymphoproliferative disease (LPD) in allogeneic stem cell transplantation (SCT) recipients. We evaluated the recovery of EBV-specific CD8+ T cells after partially T-cell—depleted SCT and studied the interaction between EBV-specific CD8+ T cells, EBV reactivation, and EBV-LPD. EBV-specific CD8+ T cells were enumerated using 12 class I HLA tetramers presenting peptides derived from 7 EBV proteins. Blood samples were taken at regular intervals after SCT in 61 patients, and EBV DNA levels were assessed by real-time polymerase chain reaction. Forty-five patients showed EBV reactivation, including 25 with high-level reactivation (ie, more than 1000 genome equivalents [geq] per milliliter). Nine of these 25 patients progressed to EBV-LPD. CD8+ T cells specific for latent or lytic EBV epitopes repopulated the peripheral blood at largely similar rates. In most patients, EBV-specific CD8+ T-cell counts had returned to normal levels within 6 months after SCT. Concurrently, the incidence of EBV reactivations clearly decreased. Patients with insufficient EBV-specific CD8+ T-cell recovery were at high risk for EBV reactivation in the first 6 months after SCT. Failure to detect EBV-specific CD8+ T cells in patients with high-level reactivation was associated with the subsequent development of EBV-LPD (P = .048). Consequently, the earlier defined positive predictive value of approximately 40%, based on high-level EBV reactivation only, increased to 100% in patients without detectable EBV-specific CD8+ T cells. Thus, impaired recovery of EBV-specific CD8+ T cells in patients with high-level EBV reactivation may identify a subgroup at very high risk for EBV-LPD and supports that EBV-specific CD8+ T cells protect SCT recipients from progressive EBV reactivation and EBV-LPD.

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.

Rituximab Prophylaxis of EBV Reactivation after Unrelated Donor Transplants Using Anti-Thymocyte Globulin in the Conditioning Regimen.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3231-3231
Author(s):  
Andrea Bacigalupo ◽  
Alida Dominietto ◽  
Monica Soracco ◽  
Sarah Pozzi ◽  
Anna Maria Raiola ◽  
...  
Keyword(s):  
Clinical Data ◽  
Lymphoblastic Leukemia ◽  
Conditioning Regimen ◽  
Lymphoproliferative Disease ◽  
Unrelated Donor ◽  
Barr Virus ◽  
Ebv Reactivation ◽  
Non Hodgkin Lymphoma ◽  
Epstein Barr ◽  
Donor Transplant

Abstract Background Epstein-Barr Virus (EBV) reactivation is a relatively common event in patients undergoing an unrelated donor transplant with anti-thymocyte globulin (ATG) in the conditioning regimen. In our first 71 patients monitored for EBV reactivartion, this occurred in 42 (59%) at a median interval of 48 days from transplant. Reactivation was higher (75%) in patients with acute lymphoblastic leukemia (ALL) non Hodgkin lymphoma (NHL) and Hodgkin’s disease (HD). When EBV reactivation exceeded 1000 copies /10^5 cells (n=12) the risk of developing a lymphoproliferative disease (LPD) was high (50%) and survival poor (30%). Aim of the study. To test whether rituximab 100 mg/m^2 given on day +5 after transplant would prevent EBV reactivation. Patients eligible for this trial were ALL, NHL and HD undergoing an unrelated donor transplant in 2004-2005, receiving ATG (Genzyme, 7.5 mg/kg) in the conditioning regimen: these patients received rituximab 100 mg/m^2 on day +5 after transplant. Controls were patients with ALL, NHL and HD allografted from similar donors between year 2000 and 2005, receiving the same dose of ATG in the conditioning. Clinical data of patients are outlined in Table 1. Clinical characteristics of controls and rituximab patients were comparable. All patients who reactivated with over 1000 copies received rituximab 375 mg/m^2 one dose, and if they did not clear EBV in 1 week, a second dose. Results. Patients receiving prophylactic rituximab on day+5 had similar neutrophil engraftment and acute GvHD as controls (Table 1). EBV reactivation occurred in 58% controls and 64% rituximab patients. There was a non significant delay of 20 days for time to reactivation (37 vs 57). The number of EBV copies at the time of reactivation was significantly higher in controls (334 vs 3, p=0.0001) and the maximum number of copies was also significantly higher in controls (1433 vs 11, p=0.001). Fourteen patients (34%) vs 1 (7%) (p=0.05) received rituximab for treatment of EBV reactivation. Transplant related mortality is 39% vs 21% (p=ns) and actuarial 1 year survival at 6 months 56% vs 63% (p=ns). Conclusions. Rituximab on day +5 significantly reduces the number of EBV copies at reactivation, without interfering with engraftment and reduces the need to treat patients for potential LPD. Table 1. Clinical data of patients Treatment group Controls Rituximab P Number 41 14 Patients age 31 27 ns ALL 27 7 NHL 7 5 HD 7 2 ns Advanced disease 75% 78% ns Day PMN 500/mmc 18 (15–31) 17 (14–21) ns GvHD grade II-IV 19% 29% 0.4 Number of EBV reactivation 24 (58%) 9 (64%) ns Day of EBV reactivation 37 (4–220) 57 (14–150) ns Copie EBV at reactivation 334 (2–5770) 3 (1–189) 0.0001 Man n. copies EBV 1433 (8–177000) 11 (3–2089) 0.001 N of patients >1000 copies 14 (34%) 1 (7%) 0.05 EBVLPD 6 (14%) 0 0.2 TRM 39% 21% 0.2 Survival at 180 days 56% 63% 0.4 Median follow up (dd) 274 131

scholarly journals Off-the-Shelf Virus-Specific T Cells to Treat BK Virus, Human Herpesvirus 6, Cytomegalovirus, Epstein-Barr Virus, and Adenovirus Infections After Allogeneic Hematopoietic Stem-Cell Transplantation

2017 ◽  
Vol 35 (31) ◽  
pp. 3547-3557 ◽  
Author(s):  
Ifigeneia Tzannou ◽  
Anastasia Papadopoulou ◽  
Swati Naik ◽  
Kathryn Leung ◽  
Caridad A. Martinez ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Epstein Barr Virus ◽  
Human Herpesvirus ◽  
Bk Virus ◽  
Third Party ◽  
Human Herpesvirus 6 ◽  
Hematopoietic Stem ◽  
Barr Virus ◽  
Epstein Barr

Purpose Improvement of cure rates for patients treated with allogeneic hematopoietic stem-cell transplantation (HSCT) will require efforts to decrease treatment-related mortality from severe viral infections. Adoptively transferred virus-specific T cells (VSTs) generated from eligible, third-party donors could provide broad antiviral protection to recipients of HSCT as an immediately available off-the-shelf product. Patient and Methods We generated a bank of VSTs that recognized five common viral pathogens: Epstein-Barr virus (EBV), adenovirus (AdV), cytomegalovirus (CMV), BK virus (BKV), and human herpesvirus 6 (HHV-6). The VSTs were administered to 38 patients with 45 infections in a phase II clinical trial. Results A single infusion produced a cumulative complete or partial response rate of 92% (95% CI, 78.1% to 98.3%) overall and the following rates by virus: 100% for BKV (n = 16), 94% for CMV (n = 17), 71% for AdV (n = 7), 100% for EBV (n = 2), and 67% for HHV-6 (n = 3). Clinical benefit was achieved in 31 patients treated for one infection and in seven patients treated for multiple coincident infections. Thirteen of 14 patients treated for BKV-associated hemorrhagic cystitis experienced complete resolution of gross hematuria by week 6. Infusions were safe, and only two occurrences of de novo graft-versus host disease (grade 1) were observed. VST tracking by epitope profiling revealed persistence of functional VSTs of third-party origin for up to 12 weeks. Conclusion The use of banked VSTs is a feasible, safe, and effective approach to treat severe and drug-refractory infections after HSCT, including infections from two viruses (BKV and HHV-6) that had never been targeted previously with an off-the-shelf product. Furthermore, the multispecificity of the VSTs ensures extensive antiviral coverage, which facilitates the treatment of patients with multiple infections.

The Impact of Monitoring Epstein Barr Virus PCR in Paediatric Bone Marrow Transplant Patients: Can It Successfully Predict Outcome and Guide Intervention.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 5064-5064
Author(s):  
Hayley M. Greenfield ◽  
Maged I. Gharib ◽  
Andrew J.L. Turner ◽  
Mary L. Coussons ◽  
Andrew M. Will ◽  
...  
Keyword(s):  
Quantitative Pcr ◽  
Immune Suppression ◽  
Epstein Barr Virus ◽  
Unrelated Donor ◽  
Barr Virus ◽  
Ebv Reactivation ◽  
Epstein Barr ◽  
High Level ◽  
The Impact ◽  
Donor Transplant

Abstract Epstein Barr Virus (EBV) associated Lymphoproliferative Disease (LPD) is a complication of allogeneic haemopoietic stem cell tranplantation (HSCT). In certain groups (congenital immunodeficiency, unrelated and mismatched donor transplants, T cell depletion) the risk may be as high as 25% with significant morbidity and mortality. Strategies to predict such illlness and allow early intervention have therefore assumed importance. We have routinely screened peripheral blood of paediatric, transplanted patients by quantitiative PCR. We report the results of such analysis of 28 successive patients and the EBV serial quantitation in 4 patients with EBV LPD. The median age at time of transplant was 6.5 years. 17 patients received an unrelated donor transplant and one patient received a haplo-identical transplant. The remainder (n=9) received a matched family donor transplant. 23 patients received either Alemtuzumab (n=19) or ATG (n=4). 13 patients had leukaemia, 5 had mucopolysaccharide syndrome, 4 for congential immune deficiency and 6 for non malignant haeamtological conditions. 9 (32%) patients showed no evidence of EBV reactivation using serial PCR monitoring. 10 patients had low level EBV reactivation as defined with a PCR log[copy number] &lt;4.5 copies/ml. 9 patients had a higher level of EBV reactivation. 2 patients had clinical EBV LPD and 2 additional LPD patients with LPD and with archived serial blood samples were also analysed. All patients with clinical LPD fell in the high level reactivation group. All patients with high level reactivation had received either Alemtuzumab or ATG. Patients within this high level group with LPD had a higher PCR log value again than those without LPD (all patients with EBV LPD had levels &gt; 6, whilst the highest level without disease was 5.2). All 4 patients responded to therapy for EBV LPD, with a combination of rituximab, withdrawal of immune suppression or administration of donor lymphocytes - DLI). At higher EBV levels the quantitative PCR had increasing positive predictive value for clinical LPD. We therefore conclude that EBV serial quantitative PCR is useful in discriminating those who will develop LPD from those that will not. Our data suggest that it is possible to use EBV PCR quantitation further to discriminate asymptomatic EBV reactivation that will resolve without therapy from EBV reactivation that will require intervention. This prevents over exposure of patients to treatments (rituximab, DLI, immune suppression withdrawal) with significant associated toxicity (prolonged B cell aplasia, graft versus host disease).

Early Response to Methotrexate, Vincristine and Procarbazine Chemotherapy-Adapted Strategy for Primary CNS Lymphoma: Omitted Radiotherapy for Patients Achieving Complete Response in Interim Analysis.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2719-2719
Author(s):  
Yu Ri Kim ◽  
Se Hoon Kim ◽  
Jong Hee Chang ◽  
Chang-Ok Suh ◽  
Soo Jeong Kim ◽  
...  
Keyword(s):  
High Risk ◽  
Whole Blood ◽  
Progression Free Survival ◽  
Complete Response ◽  
High Dose ◽  
High Risk Patients ◽  
Barr Virus ◽  
Risk Patients ◽  
Ebv Dna ◽  
Epstein Barr

Abstract Abstract 2719 The aim of this study was to evaluate treatment outcomes and prognostic factors of high-dose MVP (methotrexate, vincristine and procarbazine) chemotherapy and response adapted intensification therapy in primary central nervous system lymphoma (PCNSL). We evaluated the expression of Epstein-Barr virus (EBV)-encoded RNA in tissue and pretreatment EBV-DNA in whole blood. Forty patients with PCNSL who treated with high-dose MVP chemotherapy were retrospectively reviewed. Additional radiotherapy or autologous stem cell transplantation were performed for the patients who could not achieve complete response (CR) at interim response (Figure 1). The median age was 55 years. CR rate was 50.0% and objective response rate was 80.0%. Two-year overall survival (OS) was 59.8% and 2-year progression free survival (PFS) was 47.1%. Grade 3 or 4 neutropenia was seen in 19 of 40 (47.5%) patients and thrombocytopenia was developed in 13 (32.5%) patients. Treatment-related mortality was occurred in 4 patients. Delayed neurotoxicity was occurred in 4 patients. Poor performance status, elevated cerebrospinal fluid protein level and whole blood EBV-DNA positivity showed inferior OS (P=0.036, P=0.022, P=0.013, respectively, Figure 2). We detected whole blood EBV-DNA in 10 (29.4%) of 34 patients. It was related with poor OS and PFS in high risk patients according to International Extranodal Lymphoma Study Group scores (P=0.015, P=0.027, respectively). This study suggests that high-dose MVP chemotherapy without intrathecal chemotherapy and response adapted strategy may be an effective regimen for the newly diagnosed PCNSL. Whole blood EBV-DNA positivity could predict the inferior outcome in high-risk patients. Figure 1: Treatment scheme HD-MVP high dose methotrexate, vincristine and procarbazine, CR complete response, CRu unconfirmed complete response, PR partial response, SD stable disease, PD progressive disease, Tx treatment, NE not evaluated, ASCT autologous hematopoietic stem cell transplantation, RT radiotherapy Figure 1:. Treatment scheme HD-MVP high dose methotrexate, vincristine and procarbazine, CR complete response, CRu unconfirmed complete response, PR partial response, SD stable disease, PD progressive disease, Tx treatment, NE not evaluated, ASCT autologous hematopoietic stem cell transplantation, RT radiotherapy Figure 2: Overall survival and progression free survival according to EBV-DNA status in high risk patients. EBV Epstein-Barr virus Figure 2:. Overall survival and progression free survival according to EBV-DNA status in high risk patients. EBV Epstein-Barr virus Disclosures: No relevant conflicts of interest to declare.

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