scholarly journals High-Dose Intravenous Acyclovir Is Safe and Effective in the Treatment of EBV Reactivation Post Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4863-4863
Author(s):  
Yu Wang ◽  
Xuemei Ye ◽  
Hong Zheng ◽  
Yan Mao ◽  
Xuemei Wang ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Immune Reconstitution ◽  
Hemophagocytic Syndrome ◽  
High Dose ◽  
Hematopoietic Stem ◽  
Ebv Reactivation ◽  
Intravenous Acyclovir ◽  
Ebv Dna

Abstract Backgroud: Reactivation of nasopharyngeal carcinoma virus (EBV) post allogeneic hematopoietic stem cell transplantation(allo-HSCT) is very common, but sustained EBV activation maybe induce EBV-associated lymphoproliferative disease (PTLD), transplant-associated hemophagocytic syndrome and thrombocytopenia after transplantation, which is extremely harmful for long-term survival. Currently, the first-line therapeutic strategy for sustained EBV activation is rituximab, but rituximab leads to increased rates of infections and delayed immune reconstitution. Therefore, for the patients with EBV-DNA copies under 1000000/mL, the pros and cons of rituximab are worth weighing. Objective: To evaluate the efficacy and safety of high-dose intravenous acyclovir in the treatment of EBV reactivation post allo-HSCT. Method: Retrospective analysis of clinical data of patients with EBV reactivation post transplantation treated with high-dose intravenous acyclovir (0.5g Q8H) in Sichuan Provincial People's Hospital from January 2019 to May 2021. A total of 49 patients post allo-HSCT from from January 2019 to May 2021 were enrolled in this study. In this population, 38 patients accepted haplo-SCT and 11 patients accepted sibling-SCT. These patients all don't suffer from PTLD and transplant-associated hemophagocytic syndrome, but are resistant to oral antiviral drugs (Acyclovir, valacyclovir, and famciclovir). Simultaneously with intravenous acyclovir, all patients received human immunoglobulin with one dose of 0.4g/kg. The clinical efficacy was evaluated as follows: Overall response(ORR) was defined as the decrease of EBV copies; Complete remission(CR) was defined as the negative turn of EBV copies; Partial response(PR), Stable disease(SD) and Progression of disease(PD) were respectively defined as the decrease, no significant change and increase of EBV copies. Results: The median transplantation time was +86 (+38 to +1587) days. The median number of EBV-DNA copies/ml was 177000 (6620-8200000). After treatment with high-dose intravenous acyclovir, 29 (59.2%) of 49 patients achieved CR, 10 (20.4%) of 49 patients achieved PR, and 10 (20.4%) of 49 patients had no response, including 2 patients with SD and 8 patients with PD. All 49 patients had responded to this regimen with 79.6% ORR. The median time of response and negative turn was 4 days (2 to 11 days) and 9 days (2 to 23 days) respectively. After 100 days for follow-up, 14 of 39 responding patients suffered from EBV activation again, and the EBV copies were higher than that when high-dose acyclovir was initiated. All 24 patients who did not turn negative were recommended with the treatment of rituximab, and 19 of 20 patients who completed treatment turned negative during the three months post acyclovir treatment. The main adverse events (AEs) of this regimen were neutropenia (CTCAE grade 2-3, 8 in 49 patients), thrombocytopenia (CTCAE grade 2-3, 10 in 49 patients), increased serum creatinine (CTCAE grade 1-2, 4 in 49 patients), phlebitis (6 in 49 patients). These AEs were all reversible, which recovered after withdrawal. There was no significant change in the counts of CD4 + T cells and CD8 + T cells before and after intravenous high-dose acyclovir. Conclusion: High-dose intravenous acyclovir is safe and effective in the treatment of EBV reactivation post allo-HSCT, although nearly half of patients still need rituximab treatment. It is a reasonable strategy for patients with oral antiviral resistance. Most patients can avoid the prescription of rituximab in the first six months post allo-HSCT, without interference of immune reconstitution. Disclosures No relevant conflicts of interest to declare.

Epstein Barr Virus (EBV) Reactivation After Reduced Intensity Conditioning (RIC) Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1259-1259 ◽  
Author(s):  
Zinaida Peric ◽  
Xavier Cahu ◽  
Patrice Chevallier ◽  
Eolia Brissot ◽  
Florent Malard ◽  
...  
Keyword(s):  
Risk Factors ◽  
Stem Cell ◽  
Viral Load ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Acute Gvhd ◽  
Hematopoietic Stem ◽  
Ebv Reactivation ◽  
Unrelated Donors ◽  
Ebv Dna

Abstract Abstract 1259 Following allogeneic hematopoietic stem cell transplantation (allo-HSCT), EBV reactivation and EBV lymphoprolipherative disease (LPD) are well recognized complications. To date, few data has been reported regarding the features of EBV LPD following RIC allo-HSCT. The aim of this study was to define the incidence and risk factors of EBV reactivation in 175 consecutive adult patients undergoing RIC allo-HSCT between January 2005 and June 2009 in our institution and to assess its impact on clinical outcome. In this series, the median age of recipients was 56 (range 18–71) years. In all, 85 patients (49%) had a myeloid malignancy, whereas 86 (49%) patients were diagnosed with lymphoid malignancies. The remaining 4 patients (2%) were treated for severe aplastic anemia. In total, 165 patients (94%) received peripheral blood stem cells (PBSC) whereas 10 patients (6%) received a bone marrow (BM) graft. 84 grafts (48%) were obtained from HLA identical sibling donors, 80 (46%) from HLA matched unrelated donors and 11 (6%) from 1 Ag HLA mismatched unrelated donors. The conditioning regimen associated fludarabine, busulfan, and ATG in 107 cases (61%), while 37 patients (21%) received fludarabine and low-dose TBI. The remaining 31 patient (18%) received different chemotherapy-based RIC regimens. EBV reactivation was defined as any EBV PCR load above 1000 copies of EBV DNA /105 cells. EBV LPD was defined as biopsy or autopsy proven post-transplantation lymphoma, or reactivation along with computerized tomography nodal or soft tissue abnormalities consistent with LPD. Patients with EBV viral load >1000 copies/105 cells on at least two consecutive occasions were treated with rituximab at a dose of 375 mg/m2 weekly until clearance of viremia. In our series, the median time to neutrophil recovery (absolute neutrophil count >0.5×109/L) was 17 (range, 6–48) days. Clinically significant grade II to IV acute GVHD occurred in 61 of cases (35%) and severe grade III to IV acute GVHD occurred in 37 of cases (21%). The cumulative incidence of EBV reactivation at 6 months after allo-HSCT was 15% (95% CI, 10–21%). EBV reactivation was observed at a median of 58 (range 0–930) days after allo-HSCT, with 27 (79%) of reactivations occurring during the first 6 months. In 141 patients (81%), the EBV load remained less than 1000 EBV copies/105 cells at all time. The remaining 34 patients (19%) experienced at least one EBV reactivation episode. Among these 34 patients, 17 patients had an EBV load superior to 1000/105 cells at a single time point after allo-HSCT. In these 17 cases, there were no concomitant clinical symptoms and the EBV load normalized spontaneously. The 17 patients who had EBV DNA levels exceeding 1000 copies/105 cells on 2 or more occasions were pre-emptively treated with a median number of 3 (range, 1–4) rituximab infusions which resulted in complete clearance of EBV viremia in all, but one patient (97%). This patient was severely immunosupressed, receiving three different immunosupressive agents and experienced both EBV and adenovirus (ADV) infection. This patient had symptoms mainly related to ADV infection, and died of multiorgan failure. Most importantly, none of the patients from this series developed EBV induced LPD. With a median follow-up of 655 (range, 92–1542) days post allo-HSCT among surviving patients, 104 patients (59%) were still alive and the overall survival (OS) was 47% at 4 years. There was no statistically significant difference in terms of OS or transplant related mortality (TRM) between patients who experienced an EBV reactivation and patients who did not (OS: log rank test, p=0.62; TRM: Gray test, p=0.99). In univariate analysis for risk factors associated with EBV reactivation only the use of ATG as part of the RIC regimen prior to allo-HSCT was significantly different between subgroups with and without EBV reactivation (Fisher's exact test, p=0.006). In the multivariate analysis, the use of ATG remained the only independent risk factor associated with EBV reactivation (Fine and Gray test; RR=4.9; 95%CI, 1.1–21.0; p=0.03). In all, we conclude that patients undergoing RIC allo-HSCT using ATG as part of the preparative regimen are at higher risk for EBV reactivation. However, this did not translate into a significant impact on outcome since monitoring of EBV viral load with quantitative PCR and early systematic pre-emptive rituximab therapy allowed for significantly reducing the risk of EBV-related LPD. Disclosures: No relevant conflicts of interest to declare.

Interleukin-10 Anergized Donor T Cell Infusion Improves Immune Reconstitution without Severe Graft-Versus-Host-Disease After Haploidentical Hematopoietic Stem Cell Transplantation.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 45-45 ◽  
Author(s):  
Rosa Bacchetta ◽  
Claudia Sartirana ◽  
Barbarella Lucarelli ◽  
Patrick Miqueu ◽  
Maria Teresa Lupo Stanghellini ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Immune Reconstitution ◽  
Cellular Therapy ◽  
Interleukin 10 ◽  
Hematopoietic Stem ◽  
Graft Versus Host ◽  
Donor T Cells ◽  
Tr1 Cells

Abstract Abstract 45 Background: Adoptive transfer of regulatory T cells is a potentially attractive alternative to conventional immunosuppressive therapy in allogeneic hematopoietic stem cell transplantation (HSCT) (Roncarolo MG., Nat Rev Immunol 2007). Among CD4+ T cells, the subset known as Type 1 regulatory T (Tr1) cells are induced in an antigen specific manner by interleukin-10 (IL-10) and suppress via production of high levels of IL-10 (Groux H., Nature 1997). The aim of this phase I/II study was to establish the safety and efficacy of a new cellular therapy with Tr1 cells in a non-randomized study. Patients and Methods: A cellular therapy protocol for the adoptive transfer of IL-10 induced alloantigen specific donor-derived Tr1 cells in patients transplanted with CD34+ selected cells from haploidentical donor, has been applied to patients with high risk hematopoietic malignancies (www.risetfp6.org). Donor T cells, anergized ex vivo toward host alloantigens, presented by monocytes (original protocol) or tolerogenic dendritic cells (modified protocol) as host antigen presenting cells, in the presence of IL-10, are infused post-transplant into the host (IL-10 DLI). The infusion is made in the absence of immunosuppression for graft-versus-host-disease (GVHD) prophylaxis, with the ultimate goal to provide immune reconstitution without severe GVHD. The infused donor T cells, at the dose of 105 CD3+ cells/kg or 3 × 105 CD3+ cells/kg, are anergic towards host-HLA antigens and contain precursors of host-specific Tr1 cells but, at the same time, comprise memory T cells able to respond to nominal and viral antigens. Results: Eighteen patients have been enrolled, sixteen received CD34+ selected cells from haploidentical donor after myeloablative conditioning. Twelve patients have been treated with IL-10 anergized cell therapy at day +30 post transplant, at the dose of 105 CD3+ cells/kg with the exception of two patients who received 3 × 105 CD3+ cells/kg. No severe immediate reactions post infusion were registered. Five patients died from infections by day +30 after Tregs cell infusion and two patients dropped out for graft rejection. Five patients achieved immune reconstitution at a median of 30,5 days (range 15–46 days) after IL-10 DLI, followed by progressive normalization of TCR repertoire, memory/naïve phenotype and T cell functions in vitro and in vivo. Acute GVHD grade III was observed in one patient who received 3 × 105 CD3+ cells/kg; GVHD grade II was observed in 4 patients who received 105 CD3+ cells/kg and were successfully immune reconstituted. The median follow-up of the IL-10 DLI treated patients is 980 days (range 291–1624); 4 patients are alive and disease free and they do not require immunosuppressive treatment. Conclusions: Cellular therapy with IL-10 anergized donor T cells has proven to be safe and feasible, and to sustain immune reconstitution associated with a reduced severity of GVHD and no occurrence of relapse. This trial represents the first step towards an extended use of Tr1 cells as adjuvant treatment in allogeneic HSCT. Disclosures: No relevant conflicts of interest to declare.

scholarly journals T-cell suicide gene therapy prompts thymic renewal in adults after hematopoietic stem cell transplantation

Blood ◽  
2012 ◽  
Vol 120 (9) ◽  
pp. 1820-1830 ◽  
Author(s):  
Luca Vago ◽  
Giacomo Oliveira ◽  
Attilio Bondanza ◽  
Maddalena Noviello ◽  
Corrado Soldati ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Immune Reconstitution ◽  
Suicide Gene ◽  
Hematopoietic Stem ◽  
Donor T Cells

Abstract The genetic modification of T cells with a suicide gene grants a mechanism of control of adverse reactions, allowing safe infusion after partially incompatible hematopoietic stem cell transplantation (HSCT). In the TK007 clinical trial, 22 adults with hematologic malignancies experienced a rapid and sustained immune recovery after T cell–depleted HSCT and serial infusions of purified donor T cells expressing the HSV thymidine kinase suicide gene (TK+ cells). After a first wave of circulating TK+ cells, the majority of T cells supporting long-term immune reconstitution did not carry the suicide gene and displayed high numbers of naive lymphocytes, suggesting the thymus-dependent development of T cells, occurring only upon TK+-cell engraftment. Accordingly, after the infusions, we documented an increase in circulating TCR excision circles and CD31+ recent thymic emigrants and a substantial expansion of the active thymic tissue as shown by chest tomography scans. Interestingly, a peak in the serum level of IL-7 was observed after each infusion of TK+ cells, anticipating the appearance of newly generated T cells. The results of the present study show that the infusion of genetically modified donor T cells after HSCT can drive the recovery of thymic activity in adults, leading to immune reconstitution.

Immune reconstitution to cytomegalovirus after allogeneic hematopoietic stem cell transplantation: impact of host factors, drug therapy, and subclinical reactivation

Blood ◽  
2003 ◽  
Vol 102 (8) ◽  
pp. 3060-3067 ◽  
Author(s):  
Morgan Hakki ◽  
Stanley R. Riddell ◽  
Jan Storek ◽  
Rachel A. Carter ◽  
Terry Stevens-Ayers ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Immune Reconstitution ◽  
Multivariable Analysis ◽  
High Dose ◽  
Steroid Use ◽  
Hematopoietic Stem ◽  
Cmv Antigenemia

Abstract Reconstitution of cellular immunity by 3 months after hematopoietic stem cell transplantation (HSCT) is a critical determinant of the long-term success of the transplantation. We analyzed the factors affecting recovery of cytomegalovirus (CMV)–specific CD4+ and CD8+ function at 3 months after HSCT by univariate and multivariable analyses including source of stem cells (bone marrow vs peripheral blood stem cells [PBSCs]), age, sex, graft-versus-host disease (GVHD), steroid use, conditioning regimens, ganciclovir use, HLA matching, circulating CMV antigenemia, absolute CD4+ and CD8+ counts, and donor CMV serology. High-dose steroids and CD4+ count less than 100 × 109/L were significant predictors of impaired CD4+ functional recovery in the multivariable analysis. High-dose steroids, bone marrow as a source of stem cells, and CD8+ count less than 50 × 109/L were associated with impaired CD8+ function in the multivariable analysis. Steroids were found to impair both CD4+ and CD8+ function in a dose-dependent manner. In the absence of high-dose steroids, low-level subclinical CMV antigenemia was found to stimulate both CD4+ and CD8+ functional recovery in recipients of ganciclovir prophylaxis. There was no difference in immune reconstitution between those who received prophylactic ganciclovir versus antigenemia-guided pre-emptive therapy. Thus, absolute CD4+ and CD8+ counts less than 100 × 109/L and 50 × 109/L, respectively; bone marrow as the source of stem cells; and high-dose steroid use all predict delayed recovery of functional T-cell immunity at 3 months after transplantation. Subclinical CMV reactivation while on ganciclovir appears to be a potent stimulator of T-cell function. These findings have implications for vaccination and adoptive-immunotherapy strategies in this population.

Infusion of Ex-Vivo Expanded Donor T Cells To Improve Graft-Derived T-Cell Reconstitution after Allogeneic Hematopoietic Stem Cell Transplantation.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3261-3261
Author(s):  
Nicolas Montcuquet ◽  
Sylvain Perruche ◽  
Benjamin Shipman ◽  
Aliette Marandin-Decock ◽  
Francis Bonnefoy ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Immune Reconstitution ◽  
Ex Vivo ◽  
Murine Models ◽  
Hematopoietic Stem ◽  
Donor T Cells

Abstract Limitations resulting from the reduced availability of related donors have been solved by the development of haplo-identical transplantation or by the use of cord blood as an alternative source of hematopoietic stem cells (HSC) to the bone marrow or peripheral blood. However, these kinds of transplantation remain associated with an impaired immune reconstitution, leading to an increased risk of infection and require an efficient modulation of post-transplant alloreactivity. In this setting, we and others demonstrated the possibility to control the alloreactivity by suicide gene transfer into donor T cells after ex-vivo T-cell culture. Such ex vivo culture was associated with the acquisition of a memory-like phenotype and with a decreased alloreactivity of gene-modified T cells, leading to an impaired potential of GvHD induction in murine models of allogeneic bone marrow transplantation (BMT). Chen and al. (Blood 2004) showed in an allogeneic BMT murine models that memory T cells were less alloreactive than naive T cells, leading to a less severe GvHD, but improved the immune reconstitution as compared with mice transplanted with bone marrow cells (BMC) only. By analogy with these results, we investigated the potential of ex-vivo expanded T cells (consisting of Con-A-activated splenocytes cultured ex vivo for 12 days in the presence of 500 UI/ml IL-2) to improve immune reconstitution without inducing GvHD. As compared with recipients of T-cell-depleted (TCD) BMC only, the administration of 106ex-vivo-expanded splenocytes (T) from CD45.1 C57Bl/6 mice together with 106 TCD-BMC from CD45.2 C57Bl/6 donors into 8 Gy-irradiated Balb/c allogeneic recipients significantly increased survival of transplanted mice at day 45 (58.3% vs 23.4% for BMC + T vs BMC only; p=0.0012, log rank test). Improved survival was associated with accelerated lymphoid and myeloid reconstitution as evidenced by day 15 lymphocyte and granulocyte blood counts: 212 (median) [range: 15–991]) vs 135 [14–632] lymphocytes/μl (p=0.0220) and 802 [6–5648] vs 114 [5–2411] granulocytes/μl (p=0.0006) for BMC + T (n=61) vs BMC only (n= 55). Importantly, FACS analysis demonstrated that enhanced lymphoid and myeloid reconstitution induced by ex-vivo expanded donor T-cells was due to enhanced donor bone-marrow-derived cells (lymphocyte and granulocyte blood counts: 129 [0–932] vs 11 [0–603] lymphocytes/μl (p=0.0014) and 801 [2–5637] vs 114 [2–2409] granulocytes/μl (p=0.0007) for BMC + T vs BMC only) and not ex-vivo expanded donor cells or residual recipient cells. Within the lymphoid compartment, enhanced reconstitution was observed mainly for CD3+CD8+ cells. Co-infusion of ex-vivo expanded donor T-cells did not induce GvHD (no GvHD-induced mortality or weight loss) while co-infusion of fresh splenocytes from CD45.1 C57Bl/6 mice induced severe GvHD (p<0.001 vs BMC only). Our results establish that ex-vivo expanded donor T-cells have a graft-facilitating effect and that they could be considered as a new cell therapy product allowing improving immune reconstitution after hematopoietic stem cell transplantation. Mechanisms involved in this graft-facilitating effect of ex-vivo expanded donor T cells remain to be elucidated.

Immune reconstitution is preserved in hematopoietic stem cell transplantation coadministered with regulatory T cells for GVHD prevention

Blood ◽  
2011 ◽  
Vol 117 (10) ◽  
pp. 2975-2983 ◽  
Author(s):  
Aline Gaidot ◽  
Dan Avi Landau ◽  
Gaëlle Hélène Martin ◽  
Olivia Bonduelle ◽  
Yenkel Grinberg-Bleyer ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Regulatory T Cells ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Immune Reconstitution ◽  
Third Party ◽  
Hematopoietic Stem

Abstract Recipient-specific regulatory T cells (rsTreg) can prevent graft-versus-host disease (GVHD) by inhibiting donor T-cell expansion after hematopoietic stem cell transplantation (HSCT) in mice. Importantly, in adult humans, because of thymus involution, immune reconstitution during the first months after HSCT relies on the peripheral expansion of donor T cells initially present in the graft. Therefore, we developed a mouse model of HSCT that excludes thymic output to study the effect of rsTreg on immune reconstitution derived from postthymic mature T cells present within the graft. We showed that GVHD prevention with rsTreg was associated with improvement of the limited immune reconstitution compared with GVHD mice in terms of cell numbers, activation phenotype, and cytokine production. We further demonstrated a preserved in vivo immune function using vaccinia infection and third-party skin-graft rejection models, suggesting that rsTreg immunosuppression was relatively specific of GVHD. Finally, we showed that rsTreg extensively proliferated during the first 2 weeks and then declined. In turn, donor Treg proliferated from day 15 on. Taken together, these results suggest that rsTreg GVHD prevention is associated with improved early immune reconstitution in a model that more closely approximates the biology of allogeneic HSCT in human adults.

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