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1.
Applying Rituximab During the Conditioning Regimen Prevents Epstein-Barr Virus Infection Following Allogeneic Hematopoietic Stem Cell Transplant in a Children's Cohort: A Retrospective Case-Control Study
Ruan, Y., Chen, L., Luo, T., Xie, D., Cao, W., Liu, X., Liu, Q., Xiao, Y., Wu, C., Wen, J., et al
Infectious diseases and therapy. 2023
Abstract
INTRODUCTION Since hematopoietic stem cell transplant (HSCT) is an important therapy for malignant and non-malignant pediatric diseases, improving transplant-related mortality remains a challenge. Currently, rituximab, a monoclonal antibody of anti-CD20, is widely used for several post-HSCT complications. However, few studies have focused on the application of rituximab before HSCT. METHODS We conducted a retrospective case-control study from January 2019 to July 2021 to determine this effect in a single center. Forty-eight patients were included in the rituximab group, with a one-to-one ratio matched to the control group. RESULTS Both the occurrence rate and cumulative incidence rate of Epstein-Barr virus (EBV) infection were significantly lower in the rituximab group than in the without-rituximab group (10.4% vs. 33.3%, p = 0.014 and 12.2% vs. 39.3% p = 0.0026, respectively). Furthermore, without the application of rituximab was identified as a risk factor for post-HSCT EBV infection via both univariate [hazard ratio (HR) = 4.17, 95%CI (1.52-11.43), p = 0.005] and multivariate analyses [HR = 4.65, 95%CI (1.66-13.0), p = 0.003]. Although the overall survival (OS) probability of the rituximab group was comparable to the without-rituximab group, a markedly improved OS of the rituximab group was found in the malignant disease subgroup (78.9% vs. 42.1%, p = 0.032). The outcomes of graft-versus-host disease, neutrophil and platelet engraftment, other viral infections, and the reconstitution of lymphocytes showed no significant differences between the two groups. CONCLUSIONS The administration of rituximab before HSCT may prevent EBV infection following HSCT.
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2.
Features of Epstein-Barr Virus and Cytomegalovirus Reactivation in Acute Leukemia Patients After Haplo-HCT With Myeloablative ATG-Containing Conditioning Regimen
Ru, Y., Zhu, J., Song, T., Ding, Y., Zhu, Z., Fan, Y., Xu, Y., Sun, A., Qiu, H., Jin, Z., et al
Frontiers in cellular and infection microbiology. 2022;12:865170
Abstract
BACKGROUND Haploidentical donor hematopoietic cell transplantation (haplo-HCT) has become a preferred option for patients without HLA-matched donors, but it increases the risk of viral reactivations. Epstein-Barr virus (EBV) and cytomegalovirus (CMV) are common viruses post-HCT, but limited data have been reported in the setting of haplo-HCT. METHODS We conducted a retrospective study enrolling acute leukemia patients who received haplo-HCT with myeloablative conditioning regimen employing ATG in our center from July 2014 to July 2017. All the patients enrolled were EBV-IgM and EBV-DNA negative but EBV-IgG positive, and so were their donors. The same went for CMV as well. RESULTS In total, 602 patients were recruited consisting of 331 with acute myeloid leukemia (AML) and 271 with acute lymphoblastic leukemia (ALL). One-year cumulative incidences of EBV (22.9% ± 2.4% vs. 27.4% ± 2.8%, P = 0.169) and CMV (24.7% ± 2.4% vs. 29.4% ± 2.8%, P = 0.190) reactivation were comparable between AML and ALL. EBV and CMV were independent risk factors for each other. In the AML group, male recipients [HR = 1.275, 95% CI (1.001-1.624), P = 0.049] and acute graft-versus-host disease [HR = 1.592, 95% CI (1.001-2.533), P = 0.049] were independent risk factors for EBV reactivation and CMV reactivation, respectively. CMV rather than EBV reactivation was related to a trend of worsened treatment-related mortality (TRM) (15.6% ± 0.1% vs. 10.2% ± 0.0%, P = 0.067) and progression-free survival (PFS) (60.6% ± 4.1% vs. 70.3% ± 2.3%, P = 0.073), while significant impacts were revealed only in the subgroup analysis. CMV reactivation resulted in a remarkable inferior 2-year overall survival (OS) (64.2% ± 5.7% vs. 77.6% ± 3.2%, P = 0.038) and PFS (55.0% ± 5.9% vs. 71.9% ± 3.4%, P = 0.042) in ALL patients. On the other hand, in the EBV+/CMV- subgroup, relapse was lower in ALL patients (8.2% ± 0.2% vs. 32.4% ± 0.8%, P = 0.010) compared with AML patients, which led to a superior 2-year OS (82.0% ± 6.2% vs. 60.3% ± 8.8%, P = 0.016) and PFS (74.5% ± 7.0% vs. 57.5% ± 8.4%, P = 0.036). CONCLUSION We concluded that EBV and CMV reactivations were frequent in acute leukemia patients after haplo-HCT, with possibly distinctive risk factors from HLA-matched HCT. There could be a potential interaction between EBV and CMV, but impacts on transplant outcomes remained complex.
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3.
Allogeneic hematopoietic stem cell transplantation with the modified myeloablative conditioning regimen for children with chronic active Epstein-Barr virus infection
Luo, Y., Wei, A., Wang, B., Zhu, G., Zhang, R., Jia, C., Yan, Y., Zhou, X., Yang, J., Qin, M., et al
Pediatric investigation. 2022;6(4):250-259
Abstract
IMPORTANCE Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is considered the only effective treatment for chronic active Epstein-Barr virus infection (CAEBV). The clinical efficacy and safety of allo-HSCT with different conditioning regimens in children with CAEBV remain unclear. OBJECTIVE To evaluate the effectiveness and safety of allo-HSCT with the modified myeloablative conditioning (MAC) regimen for children with CAEBV and also the factors affecting the outcomes. METHODS We retrospectively analyzed children with CAEBV who underwent allo-HSCT with the modified MAC regimen at Beijing Children's Hospital, Capital Medical University from October 2016 to June 2021. Data related to the clinical manifestations, engraftment, and outcome were extracted from the medical records. RESULTS The cohort comprised 41 patients (24 males, 17 females) with a median transplantation age of 92.6 (60.4, 120.7) months and a median follow-up time of 28.2 (15.3, 40.2) months. Four patients (9.8%) died, among which three died from primary disease relapse, and one died from grade IV acute graft-versus-host diseases (aGVHD) after stopping treatment. The 3-year overall survival (OS) and 3-year event-free survival (EFS) rates were 88.8% ± 5.4% and 85.0% ± 5.7%, respectively. The 3-year OS and EFS did not significantly differ between the patients with hemophagocytic lymphohistiocytosis (HLH) and the patient without HLH (87.7% ± 6.8% vs. 91.7% ± 8.0%, P = 0.790; 85.0% ± 6.9% vs. 84.6% ± 10.0%, P = 0.921), or among the patients with complete remission, partial remission, and activity disease before HSCT (all P > 0.05). Multivariate analysis showed that grade III-IV aGVHD was a risk factor for mortality (Hazards ratio: 11.65, 95% confidence interval: 1.00, 136.06; P = 0.050). INTERPRETATION Allo-HSCT with the modified MAC regimen is safe and effective for pediatric CAEBV. This treatment benefits patients with HLH or active disease. Patients with Grade III-IV aGVHD may be associated with worse outcomes.
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4.
Natural history of EBV replication and viral load dynamics after alemtuzumab based allogeneic stem cell transplantation
Marzolini, M. A. V., Wilson, A. J., Sanchez, E., Carpenter, B., Chakraverty, R., Hough, R., Kottaridis, P., Morris, E. C., Thomson, K. J., Peggs, K. S.
Transplantation and cellular therapy. 2021
Abstract
BACKGROUND Epstein-Barr virus (EBV) load monitoring post-allogeneic haematopoietic stem cell transplantation (HSCT) enables earlier detection of EBV replication and is often used as a trigger for pre-emptive therapies aiming to reduce EBV-related diseases. Our institutional strategy is to treat patients with clinical signs of EBV-related disease accompanied by a rising viral load, rather than to intervene solely based on viral load. This affords an opportunity to study the natural history of EBV replication and to assess if our strategy reduces over-treatment without compromising outcomes. OBJECTIVE Our objective was to assess the natural history of untreated EBV replication in patients who have received an alemtuzumab-based allogeneic haematopoietic stem cell transplant and to examine whether our clinical strategy reduced over-treatment without compromising patient outcomes. STUDY DESIGN We present a retrospective, single-centre, observational study of 515 consecutive patients (=18 years) undergoing T-cell depleted allogeneic haematopoietic stem cell transplantation incorporating alemtuzumab. Patients underwent surveillance monitoring for EBV by qPCR in the peripheral blood at least weekly up to 100 days post-transplant and longer if they remained on immunosuppressive therapy. Cumulative incidence of EBV detection and EBV-related disease were assessed. RESULTS 192 patients had EBV DNA detectable on =1 occasion, with a cumulative incidence of 35.8% (31.8-40.4%), although this remained below the limit of quantification in 93 patients. Median time to first detection was 89.5 days (0-2254 days). The incidence was higher in sibling donor transplants (45.4% vs 30%, P= 0.00021) when compared to unrelated donor transplants. 20 patients developed EBV-related disease (cumulative incidence 3.9%). Two had immunosuppression reduction alone, 18 received rituximab, and 5 required additional therapies. Five patients died due to PTLD and all five had received rituximab. The positive predictive value of EBV load for disease was higher in the unrelated donor cohort but remained <75% regardless of EBV threshold (57.1-72.7%). CONCLUSIONS The cumulative incidence of EBV-related disease in our study (3.9%) was comparable to other studies incorporating alemtuzumab and our clinical strategy reduced over-treatment in this patient population. There are limitations of PCR-based surveillance strategies as reflected in the relatively low sensitivity of the assay coupled with the low positive predictive value which may influence the potential choice of threshold for pre-emptive intervention. We conclude that it remains unclear whether treatment based on rising EBV viral load alone gives superior overall results to treatment based on the development of clinical signs of EBV-related disease in the context of a rising viral load.
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5.
Efficacy of allogeneic hematopoietic stem cell transplantation with cocktail conditioning regimen for the treatment of pediatric patients with chronic active Epstein-Barr virus: A retrospective observational study
Fan, S., Chen, J., Liu, Z., Xiao, J., Jiang, F., Liu, X., Sun, Y.
Stem cells and development. 2021
Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) was considered as an only therapeutic strategy for chronic active Epstein-Barr virus (CAEBV) infection with few exceptions, while efficacy of various allo-HSCT conditioning regimens for CAEBV has not been fully investigated yet. This study aimed to compare the effectiveness of cocktail conditioning regimen (CCR)-allo-HSCT with reduced-intensity conditioning regimen (RICR)-allo-HSCT for pediatric patients with CAEBV. Data of a total of 54 children with CAEBV from July 2015 to December 2020, were retrospectively analyzed. Among them, 32 patients received VP16, total body irradiation (TBI), busulfan, fludarabine, cyclophosphamide, and anti-thymocyte globulin (ATG) (CCR1 group), 10 patients received VP16, ara-C, TBI, busulfan, fludarabine, cyclophosphamide, and ATG (CCR2 group), and the remaining 12 patients received VP16, busulfan or melphalan, fludarabine, and ATG with or without ara-C (RICR group). The overall survival (OS), hematopoietic engraftment, the incidence of severe graft-versus-host disease (GVHD), and other parameters were analyzed. After adjusting for potential confounders, CCR1 (hazard ratio (HR): 0.023; 95% confidence interval (CI): 0.001-0.448; P=0.013) and CCR2 (HR: 0.028; 95%CI: 0.002-0.457; P=0.012) were associated with a longer OS than RICR. The use of CCR could markedly improve the engraftment success rate and OS rate compared with RICR for pediatric patients with CAEBV.
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6.
Real-world evidence of cytomegalovirus reactivation in non-Hodgkin lymphomas treated with bendamustine-containing regimens
Pezzullo, L., Giudice, V., Serio, B., Fontana, R., Guariglia, R., Martorelli, M. C., Ferrara, I., Mettivier, L., Bruno, A., Bianco, R., et al
Open medicine (Warsaw, Poland). 2021;16(1):672-682
Abstract
Cytomegalovirus (CMV) reactivation during chemotherapy or after organ or hematopoietic stem cell transplantation is a major cause of morbidity and mortality, and the risk of reactivation increases with patients' age. Bendamustine, an alkylating agent currently used for treatment of indolent and aggressive non-Hodgkin lymphomas, can augment the risk of secondary infections including CMV reactivation. In this real-world study, we described an increased incidence of CMV reactivation in older adults (age >60 years old) with newly diagnosed and relapsed/refractory indolent and aggressive diseases treated with bendamustine-containing regimens. In particular, patients who received bendamustine plus rituximab and dexamethasone were at higher risk of CMV reactivation, especially when administered as first-line therapy and after the third course of bendamustine. In addition, patients with CMV reactivation showed a significant depression of circulating CD4(+) T cell count and anti-CMV IgG levels during active infection, suggesting an impairment of immune system functions which are not able to properly face viral reactivation. Therefore, a close and early monitoring of clinical and laboratory findings might improve clinical management and outcome of non-Hodgkin lymphoma patients by preventing the development of CMV disease in a subgroup of subjects treated with bendamustine more susceptible to viral reactivation.
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7.
Impact of alemtuzumab dosing and low-dose total body irradiation on cytomegalovirus infection in allogeneic hematopoietic stem cell transplantation
Brown, M., Abasov, R., Salerno, D., Shore, T. B., Gergis, U., Mayer, S., Phillips, A., Hsu, J., Kodiyanplakkal, R. P. L., Pasciolla, M., et al
Leukemia & lymphoma. 2020;:1-3
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8.
The association of conditioning regimen with cytomegalovirus reactivation after allogeneic hematopoietic stem cell transplantation
Mardani, M., Abolghasemi, S., Shabani, S., Tavakoli, F., Saeedi, A., Parkhideh, S., Hajifathali, A.
Iranian journal of microbiology. 2020;12(6):636-643
Abstract
BACKGROUND AND OBJECTIVES Infections is yet one of the life-threatening complications of the hematopoietic stem cell transplantation (HSCT). The myeloablative and immunosuppressive conditioning regimens, which are administered before HSCT, dampen the defense capacity of the recipients' immune systems. In this condition, opportunistic infections, especially viral infections such as cytomegalovirus (CMV) can be reactivated and cause morbidity and mortality in HSCT patients. Here, we aimed to find out any possible relationship between types of conditioning regimen and CMV reactivation in allogeneic HSCT patients. MATERIALS AND METHODS We retrospectively analyzed the data of 145 CMV-seropositive cases out of total 201 allo-HSCT patients, including age, gender, underlying disease, conditioning regimen, prophylaxis regimen and occurrence of acute graft-versus-host disease (aGVHD) to evaluate their roles in CMV reactivation. RESULTS Our result showed that conditioning regimen containing Busulfan and Fludarabine (P=0.003) or Cyclophospha-mide (P=0.02) significantly decrease the early CMV reactivation. Patients who developed aGVHD (P=0.003) and those who received anti-thymocyte globulin (ATG) as prophylaxis regimen (P=0.002), had 1.84 and 2.63 times higher risks of CMV reactivation, respectively. CONCLUSION Our findings suggest the conditioning regimen, aGVHD and ATG as influencing factors for early CMV reactivation post-HSCT which should be considered in the future studies.
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9.
Reduction of Thymoglobuline from 7.5 mg/kg to 6 mg/kg in conditioning regimen extended time to the first cytomegalovirus detection after allogenic haematopoietic stem cell transplantation
Vejrazkova, E., Hubacek, P., Pliskova, L., Kostal, M., Zavrelova, A., Stepanova, V., Zak, P.
Epidemiologie, mikrobiologie, imunologie : casopis Spolecnosti pro epidemiologii a mikrobiologii Ceske lekarske spolecnosti J.E. Purkyne. 2019;68(2):71-74
Abstract
INTRODUCTION The optimal dosage of anti-thymocyte globulin (ATG) may influence the outcome of patients after allogenic haematopoietic stem cell transplantation (HSCT). The aim of our study was to analyse human cytomegalovirus (CMV) infection data, incidence of graft-versus-host disease and other clinical endpoints comparing two patients cohorts that were administered two different Thymoglobuline Genzyme doses as part of the HSCT conditioning regimen. MATERIALS AND METHODS Total of 65 adult patients received ATG (7.5 mg/kg or 6 mg/kg) as a part of the fludarabine/busulfan/ATG conditioning regimen. CMV DNAemia was monitored after HSCT using quantitative real-time PCR and preemptive treatment was started for viral loads above 1000 cp/ml. RESULTS The mild ATG dose reduction extended the time to the first CMV detection after transplantation (28 days for 7.5 mg/kg dose vs. 40 days for 6 mg/kg dose, p = 0.04). But it did not reduce the incidence or influence first anti-CMV treatment onset, the initial viral load, peak viral load in whole blood or the antiviral therapy parameters (all p 0.18). No impact of ATG dose reduction on incidence of graft-versus-host-disease, relapse of underlying disease or mortality within first year after transplantation (all p 0.32) were observed. CONCLUSIONS The reduced ATG dosages can allow lower toxicity of conditioning regimen while keeping the performance.
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10.
EBV-PTLD, Adenovirus, and CMV in Pediatric Allogeneic Transplants With Alemtuzumab as Part of Pretransplant Conditioning: A Retrospective Single Center Study
Cupit-Link, M. C., Nageswara Rao, A., Warad, D. M., Rodriguez, V., Khan, S.
Journal of pediatric hematology/oncology. 2018
Abstract
The risk of viral infections and reactivation occurring in the setting of pediatric allogeneic hematopoietic stem cell transplantation is a concern in the pediatric patient, especially with the use of Alemtuzumab (Campath) as a conditioning agent. The purpose of this study was to determine the incidence of Epstein-Barr virus posttransplant lymphoproliferative disorder (EBV-PTLD), cytomegalovirus (CMV), and adenovirus among pediatric recipients of alemtuzumab at our institution. We found that EBV-PTLD occurred in 2.1% of transplants (1 matched unrelated donor [MUD] recipient), CMV reactivation occurred in 12.5% of transplants (4 MUD and 2 matched related donor [MRD] recipients) with disseminated CMV in 2.1% of cases (1 MRD recipient), and adenovirus infection occurred in 8.3% of the total transplants (2 MUD and 2 MRD recipients). Alemtuzumab continues to be used as a method of graft-versus-host disease and graft failure prevention among pediatric recipients of hematopoietic stem cell transplantation and seems to be safer than previously reported. At our institution, alemtuzumab has not increased the risk for EBV-PTLD, CMV infection, or adenovirus.