Preemptive Ganciclovir Therapy Research Articles

Use of Specific T Lymphocytes in Treating Cytomegalovirus Infection in Hematopoietic Cell Transplant Recipients: A Systematic Review

Cytomegalovirus (CMV) poses a significant threat to post-hematopoietic cell transplantation (HCT). Control strategies include letermovir prophylaxis or ganciclovir pre-emptive therapy (PET). Without prophylaxis, 65–90% of seropositive recipients develop a clinically significant CMV infection. Due to PET drawbacks, letermovir prophylaxis is preferable, as it reduces CMV-related events and improves overall survival. However, refractory or resistant CMV-CS remains a challenge, with maribavir showing limited efficacy. This systematic review followed the Cochrane Manual and PRISMA guidelines and was registered in PROSPERO. Searches were conducted in PubMed, Scopus, Embase, and Web of Science. Out of 1895 identified records, 614 duplicates were removed, and subsequent screening excluded 1153 studies. Eleven included studies (2012–2024) involved 255 HCT recipients receiving adoptive immunotherapy (AI), primarily CMV-specific T-cell therapy. GvHD occurred in 1.82% of cases. Adverse events occurred in 4.4% of cases, while mild CRS was observed in 1.3% of patients. Efficacy, evaluated in 299 patients across eleven studies, showed an average response rate of 78.2%. CMV-CS recurrence was observed in 24.4% of 213 patients, and death due to CMV was reported in 9.7% of 307 patients across nine studies. Adoptive hCMV-specific T-cell immunotherapy appears to be a safe, effective alternative for refractory CMV-CS in HCT.

Clinical significance of late CMV disease in adult patients who underwent allogeneic stem cell transplant

IntroductionLate cytomegalovirus (CMV) disease, which was defined as CMV disease occurring >100 days post-transplant, remains an important complication among allogeneic stem cell transplant recipients, even now that the prophylactic strategy using ganciclovir preemptive therapy has been established. Due to the recent expansion of donor sources and conditioning regimens, it is therefore appropriate to reevaluate the incidence, risk factors, and clinical impacts of late CMV disease. MethodsThis study included the 1295 adult patients, who underwent transplant for the first time from 2008 to 2015, without underlying disease relapse or CMV disease within 100 days post-transplant. There were no restrictions on underlying diseases or transplant procedures. ResultsDuring the median follow-up period of 48.4 months, 21 patients developed late CMV disease and the 5-year cumulative incidence of late CMV disease was 1.6%. By multivariate analysis, haploidentical related donor, adult T-cell leukemia lymphoma, and preemptive therapy before 100 days post-transplant were extracted as independent risk factors. Late CMV disease negatively affected transplant outcomes, and was identified as an independent risk factor for the non-relapse mortality rate (hazard ratio 3.83, p < 0.001) and overall survival rate (hazard ratio 4.01, p < 0.001). Although 17 of 21 patients with late CMV disease died, the main causes of death were not related to CMV, except in three patients with CMV pneumonia. ConclusionsAlthough the incidence of late CMV disease is low in transplant recipients, this complication negatively affects clinical courses. Therefore, transplant recipients with these risk factors should be more carefully managed.

Cytomegalovirus management after allogeneic hematopoietic stem cell transplantation: A mini-review

Because of the high incidence of cytomegalovirus (CMV) seropositivity in the population, CMV infection is a common and severe complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in Taiwan. Here we propose a CMV management strategy for patients undergoing allo-HSCT from the Taiwanese perspective, which focuses on the epidemiology, diagnosis, monitoring, prophylaxis, and treatment of CMV infection after allo-HSCT. In terms of CMV monitoring, weekly CMV monitoring with the COBAS® AmpliPrep system is the standard approach because the pp65 CMV antigenemia assay has a lower sensitivity than CMV monitoring with the COBAS® AmpliPrep system. However, pp65 CMV antigenemia assay has a better correlation with clinical symptoms in immunocompromised patients. A 14-week prophylactic course of letermovir is recommended for allo-HSCT recipients in Taiwan, especially for recipients of hematopoietic stem cells from mismatched unrelated and haploidentical donors. Preemptive ganciclovir therapy should be initiated when the CMV viral load exceeds 1000 copies/mL, and should not be discontinued until CMV DNA is no longer detected in the blood. For allo-HSCT recipients who have CMV-related diseases, ganciclovir with or without CMV-specific intravenous immunoglobulin is the standard of care. The limited availability of foscarnet, an alternative for patients who are not responsive to or cannot tolerate ganciclovir, is a crucial issue in Taiwan. For pediatric allo-HSCT recipients, more data are needed to propose a CMV management recommendation.

1106. The incidence and risk factors associated with varicella zoster virus infection in kidney transplant recipients after 1-month acyclovir prophylaxis in a CMV preemptive therapy era

BackgroundVaricella zoster virus (VZV) infection is a well-known opportunistic infection in solid organ transplant recipients. Since the various strategies of the use of anti-herpetic drugs including ganciclovir or acyclovir have evolved, the epidemiology of VZV infection is changing. However, there are limited data on the recent incidence and risk factors of post-transplant VZV infection in popular preemptive ganciclovir era for CMV infection. We evaluated the incidence, risk factors and clinical characteristic of patients with development of post-transplant VZV infection in kidney transplant (KT) recipients after 1-month acyclovir prophylaxis in the hospital that adopted preemptive ganciclovir therapy for CMV infection.MethodsAll adult patients with seropositive CMV antibody admitted to a KT unit from January 2014 to December 2017 were retrospectively reviewed in a tertiary-care hospital in South Korea. Our hospital adopted preemptive ganciclovir therapy for CMV infection in all CMV seropositive KT recipients. We administered acyclovir prophylaxis for 1-month to CMV seropositive KT recipients. The primary endpoint was VZV infection development after KT.ResultsA total of 1295 KT recipients was followed up for 4295.8 person-years. The median follow-up period was 46.6 months (interquartile range (IQR) 34.3-59.5). Of the 1295 recipients, 100 (7.7%, 2.33 per 100 person-years, 95% confidence interval (CI) 1.89-2.83) patients developed VZV infection after KT. The median time for VZV infection development was 9.5 months (IQR 4.7-22.1). All patients had VZV-associated skin lesion, 9 postherpetic neuralgia, 2 visceral involvement and 3 disseminated infection. Of 100 patients, 16 patients need hospitalization due to VZV infection. In multivariate analysis, deceased donor KT (Hazard ratio (HR) 1.6; 95% CI 1.0-2.39, p = 0.05), mycophenolate maintenance immunosuppressive therapy (HR 0.3; 95% CI 0.14-0.75, p = 0.01) and rejection episode (HR 0.31; 95% CI 0.14-0.71, p = 0.01) were independently associated with VZV infection development after KT.ConclusionAbout one tenth of CMV seropositive KT recipients developed zoster after 1-month ACV prophylaxis during CMV preemptive strategy, especially in those who received deceased donor KT, mycophenolate therapy, and rejection episodes.Disclosures All Authors: No reported disclosures

Comparing Costs Associated to Letermovir Prophylaxis Vs Ganciclovir Pre-Emptive Therapy in HCMV-Seropositive Patients Who Undergone to Hemopoietic Stem Cells Transplantation

INTRODUCTION: Human cytomegalovirus (HCMV) infection is a significant cause of mortality and morbidity after hemopoietic stem cell transplantation (HSCT). Pre-emptive therapy with Ganciclovir (GCV) reduces the risk for HCMV disease but may be associated with significant toxicity. Letermovir (LTV) has been recently approved for prophylaxis of HCMV infection in HCMV-seropositive patients. AIM: to compare costs associated with GCV preemptive therapy or LTV prophylaxis within 100 days after HSCT. METHODS: A retrospective analysis of GCV preemptive therapy-related costs was performed on 63 HCMV-seropositive patients receiving allogeneic HSCT. For comparison, we estimated LTV prophylaxis-related costs according to dosage and duration reported in the phase 3 trial (Marty et al., NEJM 2017). According to definitions adopted in the LTV prophylaxis study, patients were considered at high risk for HCMV-disease if having one of the following: a mismatched (related or unrelated) or a haploidentical donor; umbilical cord blood as the stem-cell source; ex vivo T-cell-depleted grafts; and grade ≥2 GVHD. Clinically significant HCMV infection was defined as HCMV disease (i.e. HCMV end-organ infection in association with clinical symptoms) or HCMV DNAemia leading to pre-emptive treatment (i.e. ≥ 30.000 copies/mL in blood in the GCV-preemptive group; ≥ 150 copies/mL or ≥ 300 copies/mL in plasma for high-risk or low-risk patients in the LTV-prophylaxis study). All diagnostic and therapeutic procedures performed within 100 days post-HSCT were recorded. Costs associated to HCMV antiviral therapy and to the management HCMV infection (including also, but not limited to, diagnostic procedures, transfusions and hospitalizations) were calculated. RESULTS Study populations Baseline characteristics of the GCV-preemptive group in comparison with the LTV-prophylaxis group are shown in Table 1. A higher proportion of patients at high risk for HCMV disease has been observed in the preemptive group (49.2% vs 32.4%). HCMV infection and disease GCV-preemptive group: 39 patients (62%) developed a clinically significant HCMV infection and in all cases pre-emptive therapy resolved the infection. Drug switch due to GCV-induced neutropenia was not necessary in any case. Gastrointestinal HCMV disease occurred beyond day 100: in 2 patients (3.2%) occurred within 24 weeks post-HSCT and in additional 7 patients later on (median time: 314, range 144-387 days after HSCT). LTV-prophylaxis group: clinically significant HCMV infection occurred in 57/325 (17.5%) patients with 5 (1.5%) developing gastrointestinal HCMV disease within 24 weeks after HSCT. Data for HCMV disease beyond week 24 are not reported. Costs analysis GCV-preemptive group: 5 mg/kg GCV has been administered i.v. twice daily. One vial of GCV 500 mg is purchased at a cost of 57.67 €. The average duration of GCV therapy was 16.9 days and the average cost was 77 €/day, i.e. 1301.67 €/patient. Six patients (10%) were hospitalized for the management of HCMV infection, for a total cost of 22,428 € (356 €/patient). Thus, the overall cost was 1657.67 €/patient (78% directly related to GCV-therapy and 22% related to the healthcare management costs). LTV-prophylaxis group: 240 mg/day of oral LTV were administered for of 100 days. Twenty-eight tablets of LTV cost of 13,863.36 €. Thus the total cost for LTV administration is 49,512 €/patient (or 24,756 € for patients receiving cyclosporine). We did not consider costs associated to HCMV reactivation. The costs for HCMV management with LTV prophylaxis appears to be ≥15 times superior to the costs for GCV preemptive therapy CONCLUSIONS: LTV prophylaxis is effective in reducing the risk for HCMV disease. However, the costs are superior to those for GCV-preemptive therapy (also considering hospitalization costs). Prospective randomized studies are needed to compare directly different outcomes in HSCT recipients receiving LTV prophylaxis vs GCV preemptive therapy (such as overall costs, indirect effects of subclinical HCMV infection, overall patient's survival). Nevertheless, the identification of patients at lower risk for HCMV infection (thus not requiring prophylaxis), as well as a personalized administration of LTV prophylaxis on the basis of the individual time to immune reconstitution (thus tailoring duration of prophylaxis), will be of great help for sparing costs in Health Systems with limited resources. Disclosures No relevant conflicts of interest to declare.

Factors associated with cytomegalovirus infection in children undergoing allogeneic hematopoietic stem-cell transplantation.

While preemptive therapy with ganciclovir (GCV) for cytomegalovirus (CMV) infection is used following allogeneic hematopoietic stem-cell transplantation (HSCT), risk factors for CMV infection in children undergoing HSCT are poorly understood.We studied CMV reactivation following allogeneic HSCT by retrospectively analyzing pediatric patients who received allogeneic HSCT and preemptive GCV therapy between 1998 and 2016. The level of viremia requiring preemptive GCV therapy was >1 CMV antigen-positive cells per 5 × 105 leukocytes during the antigenemia assay era and >1000 copies/mL in the polymerase chain reaction era. Among 290 at-risk patients, 54 (18.6%) patients had primary CMV infection or CMV reactivation occurring at a median of 76 days (range, 7–234) following HSCT. CMV reactivation occurred in 28.2% (44/156) of CMV-seropositive transplant recipients at a median of 26 days posttransplant.Univariate and multivariate analyses revealed statistically significant relationships between CMV infection and grade III–IV acute graft-vs-host disease, seronegative donor/seropositive recipient combination, and unrelated/mismatched donors. The remaining demographic factors were not predictive of CMV infection.The seronegative donor/seropositive recipient combination for HSCT was associated with an incomplete response to antiviral therapy. Human leukocyte antigen identical donors were the best choice for patients undergoing allogeneic HSCT to reduce the incidence of CMV disease and mortality.

Thymoglobulin Versus Basiliximab Induction Therapy in Low-Risk Kidney Transplant Recipients: A Single-Center Experience

BackgroundThe Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend that T-cell–depleting agents should be used only for kidney transplant (KT) recipients at high immunologic risk. However, the effects of thymoglobulin induction therapy in low–immunologic risk KT recipients on tacrolimus, mycophenolic acid, and steroid have not been elucidated yet. MethodsWe retrospectively collected 6 months postoperative clinical data, for low–immunologic risk KT recipients at Soonchunhyang University Hospital. Recipients were divided into thymoglobulin and basiliximab groups, based on the induction agent used. Low–immunologic risk recipients were defined as those with panel-reactive antibody level <30% at the time of kidney transplantation. The incidence of biopsy-proven acute rejection and borderline change was compared between the two groups. ResultsOf the 46 low–immunologic risk patients, 25 received thymoglobulin. The incidence of biopsy-proven acute rejection was 0% (n = 0) and that of borderline change was 8% (n = 2) in the thymoglobulin group. The basiliximab group had a significantly higher incidence of rejection (23.8%; n = 5; P = .015) and borderline change (42.9%; n = 9; P = .006). No significant difference in estimated glomerular filtration rate was found between the two groups at 6 months after kidney transplantation. Cytomegalovirus (CMV) infection occurred more frequently in the thymoglobulin group than in the basiliximab group. All patients with CMV infection in both groups were effectively treated with pre-emptive intravenous ganciclovir therapy. ConclusionsIn low–immunologic risk KT recipients who received tacrolimus, mycophenolic acid, and steroid therapy, thymoglobulin induction therapy significantly reduced the incidence of biopsy-proven acute rejection and borderline change compared with basiliximab induction therapy.

Rapid regression of cystoid macular edema associated with cytomegalovirus retinitis in adult acute myeloid leukemia by intravitreal methotrexate combined with oral valganciclovir: A case report with comparison of binocular outcome

Cytomegalovirus (CMV) retinitis is a late complication of organ and hematopoietic stem cell transplant, the risk of which depends on the degree of immunosuppression. With the institution of preemptive ganciclovir therapy early after transplant, most patients survive episodes of life-threatening CMV infection during the early months (usually the first 3 months) after transplant and hence late onset of CMV disease, such as CMV retinitis, is being recognized more frequently. Direct involvement of the macula or optic head remains the leading cause of visual loss in patients with CMV retinitis, but there are few studies investigating the management of this condition.Herein, we present the case of 28-year-old man who had acute myeloid leukemia and developed CMV retinitis with bilateral cystoid macular edema and optic swelling in the right eye 6 months after bone marrow transplant. He received treatment with intravitreal methotrexate in the right eye in combination with oral valganciclovir. Visual acuity improved 1 month after four weekly injections of intravitreal methotrexate 400 μg/0.1 mL. Resolved disc swelling and regression of macular edema were also observed. By comparing binocular outcome, we present our findings and discuss the possible efficacy and safety of this treatment with respect to regression of anatomical damage and improvement in visual acuity.

The Incidence of Venous Thromboembolism (VTE) in 892 Allogeneic Hematopoietic Cell Transplant (allo-HCT) Recipients ( A single institution study comparison of VTE incidence with sirolimus versus non-sirolimus-based GVHD prophylaxis)

s / Biol Blood Marrow Transplant 21 (2015) S266eS321 S297 multivariate analysis using the LASSO approach to logistic regression analysis. Results: Of 134 allo-HSCTs, 29 (21.6%) patients experienced CMV viremia. Among these patients, median age was 51 years (range 27-67), with 48 episodes of viremia. Nine (31%) viremic patients developed CMV disease. CMV disease occurred at a median of 124 days post HSCT (range 61-322). Patients with CMV disease had a median of 2 viremic episodes before disease (range 1-4). Disease occurred at a median of 33 days from the start of the last viremic episode, and 75 days from the start of the first episode of viremia. On univariate analysis, factors associated with progression to CMV disease were: steroid-refractory acute GVHD (60 vs. 20%, p1⁄40.028); number of episodes of viremia >1x103 copies/mL (mean 2.4 vs 1.1, p1⁄40.016); longer duration of viremia (mean 38 vs. 22 days, p1⁄40.01); higher peak viral load (mean 4.49x105 vs. 8.31x103 copies/mL, p 1x103 copies/mL, a longer duration of viremia, and to have failed first-line pre-emptive ganciclovir therapy. This study, while limited, suggests that these risk factors may be predictive of CMV disease. Larger, prospective studies are needed to confirm these risk factors, some of which may be amenable to more aggressive anti-viral therapy.

Full Donor Myeloid Engraftment with Minimal Toxicity in Dyskeratosis Congenita Patients Undergoing Allogeneic Bone Marrow Transplantation without Radiation or Alkylating Agents

Dyskeratosis congenita (DC) is an inherited bone marrow failure (BMF) syndrome caused by defects in telomere biology genes. BMF occurs in approximately 80% of patients by 30 years of age and, in addition to pulmonary failure and malignancies, remains a major contributor to mortality. Hematopoietic cell transplantation (HCT) cures BMF in DC patients but is associated with a high incidence of graft failure and transplant-related mortality. Radiation and/or alkylating agents (e.g. cyclophosphamide, busulfan, melphalan) used in conditioning may have a role in the poor outcomes in DC patients following HCT. Recently, reduced-intensity conditioning approaches have improved short-term outcomes, but concerns remain about the long-term effects of DNA damaging agents in these regimens, given the multisystem disease and lifelong predisposition to malignancy conferred by telomere dysfunction.Radiation and alkylating agents are mainstays of allogeneic HCT preparative regimens: their highly effective myeloablative and immunosuppressive properties provide a niche for donor hematopoietic progenitors and decrease graft rejection. Based on a rationale that presumes (1) niche availability in DC patients with BMF, and (2) an intrinsic replicative defect in DC hematopoietic cells, we hypothesized that engraftment would be feasible in DC patients using a regimen of immunosuppressive therapy alone.Here, we report that in a single-institution prospective study, 4 consecutive patients with DC have undergone successful HCT using a radiation- and alkylator-free preparative regimen. Patients received alemtuzumab and fludarabine, followed by bone marrow transplantation (BMT) from unrelated donors. Cyclosporine A and mycophenolate mofetil were used for graft versus host disease (GVHD) prophylaxis. The primary outcome measures were neutrophil engraftment at day +30 and overall survival at day +100. Secondary outcome measures included acute toxicities and rates of graft failure, infections, and GVHD.The first two patients were 18 month-old twins with TINF2 mutations and transfusion-dependent BMF who received a BMT from a fully HLA-matched unrelated donor. The third patient was an 18 year-old female with CTC1 mutations and transfusion-dependent BMF, who underwent a B-mismatched unrelated donor BMT. The fourth patient, a 22 year-old male with clinical DC and short telomeres, had significant pulmonary disease (diffusing capacity of lung for carbon monoxide 28% of predicted) and BMF, and underwent a fully HLA-matched unrelated donor BMT.All 4 patients engrafted neutrophils by day +30, and are alive and well with follow-up ranging from 6 months (1 patient) to 2 years (3 patients). Platelet transfusion-independence occured between day +4 to +18, and red cell transfusion-independence occured between day 0 to +90. No patients required transfusions thereafter. All patients showed full donor myeloid chimerism by day +60. 3 of 4 patients showed full donor lymphoid chimerism by year 2; the fourth patient has high and increasing mixed donor lymphoid chimerism (60%) at day +180. There were no significant, unexpected toxicities, bacterial or fungal bloodstream or tissue infections. All patients were monitored weekly by serum PCR for CMV, EBV, adenovirus and HHV6 until day +100; only one patient showed CMV reactivation which was controlled with pre-emptive ganciclovir therapy. There was no acute GVHD. Only one patient developed chronic GVHD with limited skin involvement controlled with topical steroids.These results provide promising early data for engraftment and a favorable short-term toxicity profile using a radiation- and alkylator-free conditioning regimen in HCT for BMF due to DC. This approach could spare DC patients the acceleration of non-hematologic complications and malignancies, which has been attributed to HCT, and improve long-term survival. The limited toxicity of the alemtuzumab/fludarabine regimen may also allow patients with severe disease-related co-morbidities such as pulmonary dysfunction to safely undergo HCT. To our knowledge, this is the first prospective HCT study to achieve full donor myeloid engraftment in a series of patients following conditioning without radiation or alkylating agents. DisclosuresOff Label Use: alemtuzumab - conditioning for bone marrow transplantation fludarabine - conditioning for bone marrow transplantation cyclosporine A - graft versus host disease prophylaxis in bone marrow transplantation mycophenolate mofetil - graft versus host disease prophylaxis in bone marrow transplantation.

Risk factors of Ganciclovir-related neutropenia after allogeneic stem cell transplantation: a retrospective monocentre study on 547 patients

Cytomegalovirus (CMV) infection is a serious complication that may occur in the weeks or months following bone marrow transplantation. However, both Ganciclovir and the CMV infection itself can cause marrow toxicity, notably neutropenia, that may consequently expose these immunosuppressed patients to life-threatening bacterial and/or fungal infections. The aim of this retrospective study was to identify factors associated with the occurrence of grade III–IV neutropenia among patients receiving pre-emptive Ganciclovir therapy after allogeneic stem cell transplantation at our Institution. We identified 547 consecutive patients transplanted from January 2005 to June 2011 at our Institution. In all, 190 patients (35%) presented with CMV reactivation of whom 30 patients (5%) were excluded from the analysis because they already had neutropenia at the time of reactivation. Finally, 160 (29%) patients were analysed. According to multivariate analysis, at the time of treatment initiation, the risk factors significantly associated with a grade III–IV Ganciclovir-related neutropenia included a high viral load (hazard ratio (HR) = 2.68, 95% CI 1.25–5.737, p 0.01); an absolute neutrophil count >3000 was a protective factor (HR = 0.26, 95% CI 0.125–0.545, p <0001) whereas serum creatinine >2 mg/dL was associated with higher Ganciclovir-related neutropenia (HR = 2.4, 95% CI 1.11–5.17, p 0.002). This large analysis revealed three risk factors for Ganciclovir-related neutropenia among patients with CMV reactivation after allogeneic stem cell transplantation; prompt identification of patients at risk when antiviral therapy is started may allow clinicians to adopt adequate preventive measures, so reducing the morbidity and mortality associated with CMV reactivation.

Impact Of CMV Reactivation On Relapse In Patients With Acute Leukemia Who Received Allogeneic Stem Cell Transplantation In First Remission: Possible GVL Effect In CMV Seropositive Population

In western countries, several studies have reported that CMV seronegative acute leukemia (AL) patients might have a beneficial effect from CMV seropositive donor for reduction of relapse. These observations resulted from subclinical CMV viremia with delayed initiation of antiviral therapy which showed a stimulatory effect on natural-killer cells and cytotoxic T-cells that may enhance graft-versus-leukemia (GVL) effect. We tried to evaluate the relationship between CMV reactivation and relapse of AL in Korean population, in which CMV serostatus is mostly positive for both donors and recipients.Three hundred eighty-nine AL patients with AML (n=197), ALL (n=192) who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first remission between 2007 and 2011 were retrospectively analyzed. Most of the donors (95.1%) and recipients (98.7%) were CMV seropositive. After engraftment, we serially measured CMV RQ-PCR once a week for surveillance of CMV reactivation and generally initiated preemptive ganciclovir (GCV) therapy when the titer reaches over 15,000copies/mL. Below 15,000, patients without GVHD were observed with tapering immunosuppressive agents. To evaluate the anti-leukemic activity of CMV viremia, patients with early death (<150 days) were excluded and subgroup analysis was performed according to the occurrence of chronic GVHD. OS, EFS and relapse incidence was compared between the 3 groups; undetected viremia, GCV-treated viremia with higher-level and untreated viremia with lower-level of CMV RQ-PCR.In the entire group, CMV viremia was an adverse factor for OS (p<0.001) and EFS (p<0.001), and patients with acute-GVHD significantly showed more CMV viremia (91.5% vs. 83.6%, p=0.017). After excluding early death (n=51), 195 patients without chronic-GVHD were finally analyzed. Untreated lower-CMV group (n=93) showed significantly superior OS (p<0.001) and EFS (p<0.001) with lower relapse rate (p=0.003) compared to the treated higher-CMV (n=72) and CMV-undetected group (n=30). Patients with other than untreated lower-CMV viremia and adverse-risk karyotype were independent adverse-risk factor for OS, EFS and relapse by multivariate analyses in subgroup without chronic GVHD. In chronic-GVHD subgroup (n=143), CMV-undetected group showed superior OS (p=0.006) and EFS (p=0.010), but the relapse rate was not significantly different (p=0.238). The results were similar in subgroup analyses for AML and ALL.Our data showed the possible GVL effect associated with CMV reactivation measured by RQ-PCR. This finding should be evaluated by larger validated studies to disclose the role of CMV reactivation in AL in the CMV seropositive population. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Efficacy of a strategy for discontinuing pre-emptive ganciclovir therapy after a negative cytomegalovirus antigenaemia test result in seropositive kidney transplant recipients

chronology of adverse effects) are consistent with bosentan overexposure. Our case of serious unexpected adverse effects with bosentan and telaprevir treatment for PAH and HCV/HBV/HIV coinfection suggests a possible deleterious DDI. The proposed alternative of ambrisentan was safe and effective 4 weeks after reintroduction of the telaprevir-containing anti-HCV tritherapy. This case highlights the difficulty in anticipating DDIs with polymedicated HCV/HBV/HIV coinfection and liver impairment.

Efficacy and safety of low-dose ganciclovir preemptive therapy in allogeneic haematopoietic stem cell transplant recipients compared with conventional-dose ganciclovir: a prospective observational study

We performed a prospective observational study comparing the efficacy and safety of low-dose ganciclovir (5 mg/kg/day) as initial preemptive therapy in allogeneic haematopoietic stem cell transplantation (HSCT) recipients with conventional-dose ganciclovir (10 mg/kg/day). All adult patients undergoing allogeneic HSCT were enrolled at a transplant centre over a 24 month period. The decision to use low-dose or conventional-dose ganciclovir was at the discretion of each attending haematologist. A logistic regression model with inverse probability of treatment weighting (IPTW) using propensity scores was performed to reduce the effect of the selection bias in assignment for ganciclovir preemptive therapy. Of the 252 HSCT recipients, 97 (38%) received preemptive ganciclovir therapy. Of these, 53 (55%) and 44 (45%) received low-dose and conventional-dose ganciclovir, respectively. The viral clearance rate was higher in the low-dose ganciclovir group [98% (52/53)] than in the conventional-dose ganciclovir group [86% (38/44), P = 0.04], while the low-dose ganciclovir group exhibited a longer viral clearance time (median 21.0 days) than the conventional-dose ganciclovir group (median 14.0 days, P = 0.05). The rate of discontinuation of therapy due to neutropenia or nephrotoxicity was similar in the two groups, although conventional-dose ganciclovir was changed to another regimen more frequently than low-dose ganciclovir. There were three cases of cytomegalovirus (CMV) disease in each group after the initial preemptive therapy. The logistic regression models using propensity scores also revealed that there were no significant differences in viral clearance, secondary episodes of CMV infection, CMV disease and overall mortality between the two groups. Low-dose ganciclovir appears to be safe, and to be at least as effective as conventional-dose ganciclovir for CMV viraemia in allogeneic HSCT recipients.

Paradoxical Rising Cytomegalovirus Antigenemia during Preemptive Ganciclovir Therapy in Hematopoietic Stem Cell Transplant Recipients: Incidence, Risk Factors, and Clinical Outcomes

Preemptive ganciclovir (GCV) therapy is adopted increasingly in hematopoietic stem cell transplant (HCT) recipients, but occasional cases of increasing cytomegalovirus (CMV) antigenemia levels occur during preemptive GCV therapy. This prospective study investigated the incidence, risk factors, and clinical outcomes of paradoxical responses during GCV therapy. Adult patients receiving allogeneic HCTs during a 24-month period were enrolled. Patients were prospectively monitored for CMV antigenemia once a week until 3 months after engraftment. Paradoxical responders were defined as patients exhibiting CMV antigenemia levels elevated from the baseline after the first week of preemptive GCV therapy. Of 252 HCT recipients, 97 (38%) received preemptive GCV therapy due to CMV infection. Of these 97 patients, 23 (24%) were classified as paradoxical responders. Risk factors for paradoxical response were a low white blood cell (WBC) count (P = 0.02) and a prolonged duration of CMV antigenemia (P = 0.04) before preemptive therapy. There were no significant differences in rates of successful viral clearance and secondary episodes of CMV infection between paradoxical responders (87% [20/23] and 26% [6/23]) and nonparadoxical responders (95% [70/74] and 23% [17/74], respectively). However, breakthrough CMV disease during preemptive GCV therapy was significantly more frequent in paradoxical responders (17% [4/23]) than in nonparadoxical responders (3% [2/74], P = 0.03). Paradoxical responses occurred in one-quarter of the HCT recipients receiving preemptive GCV therapy. A low WBC count and a long duration of CMV antigenemia before GCV therapy were associated with paradoxical responses, and breakthrough CMV disease during preemptive GCV therapy occurred more frequently in paradoxical responders.

Pre-emptive intravenous ganciclovir versus valganciclovir prophylaxis for de novo cytomegalovirus-seropositive kidney-transplant recipients

This sequential study evaluated two strategies regarding human cytomegalovirus (HCMV) infection/disease in HCMV-seropositive de novo kidney-transplant patients. The first cohort of patients (group 1; n = 132) was monitored sequentially for HCMV DNAemia; if it was positive (a cut-off at 3 log(10) copies/ml), the patient was given pre-emptive IV ganciclovir therapy (10 mg/kg/day for 3 weeks). The second cohort consisted of 150 patients (group 2) who were given valganciclovir (VGC) prophylaxis (900 mg/day) for the first 3 months posttransplantation. During the mean follow-up of at least 2 years for both cohorts, VGC prophylaxis resulted in a significant decrease in both CMV infection (68.9% vs. 33.3%; P < 0.001) and disease (9.8% vs. 2.68%, P = 0.021). Factors associated with HCMV reactivation in multivariate analysis were (i) no HCMV prophylaxis; (ii) recipient's age; (iii) being placed on ciclosporine A and mycophenolic acid from the beginning of transplantation (iv) donor HCMV-seropositivity; and (v) being a male recipient. No cases of ganciclovir resistance were detected in the prophylactic group. HCMV prophylaxis had no impact on 2-year patient/graft survival or on kidney-allograft function. We conclude that VGC-prophylaxis can be reasonably used to treat HCMV-seropositive kidney-transplant recipients.

A randomized trial of preemptive therapy for prevention of cytomegalovirus disease after allogeneic hematopoietic stem cell transplantation

We studied the efficacy of two different doses of ganciclovir to prevent cytomegalovirus (CMV) disease in allogeneic hematopoietic stem cell transplantation (HSCT) recipients. We randomly assigned allogeneic HSCT recipients who had CMV infection to receive preemptive ganciclovir therapy with or without induction phase (5 mg/kg twice daily for 1 week). Thirty-two and thirty-six patients were randomized to the standard and the low-dose therapy group, respectively. The median time to CMV antigenemia or viremia clearance was 7 days (3-25 days) in the standard therapy group versus 11 days (3-69 days) in the low-dose therapy group (P = 0.540). The incidence of CMV disease was similar between the two groups (P = 0.366). The Kaplan-Meier estimate of event-free survival by day 180 after HSCT was 76.2% in the standard therapy group versus 66.7% in the low-dose therapy group (P = 0.590). Severe neutropenia (<0.5 x 10(9)/L) was observed in four (12.5%) patients in the standard therapy group versus two (5.6%) patients in the low-dose therapy group (P = 0.314). This study suggests that a low-dose ganciclovir preemptive therapy can be as effective as the standard-dose ganciclovir preemptive therapy for the prevention of CMV disease in allogeneic HSCT recipients.

CMV central nervous system disease in stem-cell transplant recipients: an increasing complication of drug-resistant CMV infection and protracted immunodeficiency

We report on two patients with no active GVHD and on moderate doses of immunosuppressive drugs who unexpectedly developed fatal CMV meningoencephalitis after umbilical cord blood transplantation. A review of these two cases along with nine other cases of CMV central nervous system (CNS) disease after allogeneic SCT that were mostly reported within the last 8 years suggests that this severe complication of CMV infection may be increasing. CMV CNS disease after allogeneic SCT is a late-onset disease (median time of onset, 210 days) and is usually manifested as encephalitis in the absence of other sites of CMV disease. The development of CMV CNS disease is associated with risk factors (T-cell depletion, anti-thymocyte globulin, umbilical cord blood transplantation) that cause severe and protracted T-cell immunodeficiency (8 of 11 cases), a history of recurrent CMV viremia treated with multiple courses of preemptive ganciclovir or foscarnet therapy (11 of 11 cases), and ganciclovir-resistant CMV infection (11 of 11 cases). Despite therapy with a combination of antiviral drugs (ganciclovir, foscarnet and cidofovir), mortality is high (10 of 11 cases). Given this high mortality, extended prophylaxis with current or novel antiviral drugs and strategies to enhance CMV immunity need to be considered in high-risk patients.

Lack of prompt expansion of cytomegalovirus pp65 and IE-1-specific IFNγ CD8+ and CD4+ T cells is associated with rising levels of pp65 antigenemia and DNAemia during pre-emptive therapy in allogeneic hematopoietic stem cell transplant recipients

Rising levels of cytomegalovirus (CMV) DNAemia and/or pp65 antigenemia have been observed during pre-emptive ganciclovir therapy in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-SCT). We assessed the incidence of this event in our series, and investigated whether its occurrence was associated with an impairment in the CMV-specific T-cell response. A total of 36 allo-SCT recipients experienced one or more episodes of active CMV infection (n=68) that were pre-emptively treated with val(ganciclovir). Rising levels of antigenemia and DNAemia, and an isolated increase in antigenemia, were observed in 39.7 and 2.9% of all episodes, respectively. Receipt of corticosteroids was associated with rising levels of antigenemia and DNAemia. Median increases of 12- and 6.8-fold of IFNgamma CD8(+) T and IFNgamma CD4(+) T cells, respectively, were observed at a median of 16.5 days after initiation of therapy in episodes with decreasing levels in antigenemia and DNAemia. In contrast, the numbers of both T-cell subsets at a median of 13.5 days after initiation of therapy did not differ significantly from those of pre-treatment samples in episodes with rising levels of antigenemia and DNAemia. Lack of prompt expansion of CMV pp65 and IE-1-specific IFNgamma CD8(+) and CD4(+) T cells is associated with rising levels in antigenemia and DNAemia during pre-emptive therapy.

Impacto de la carga vírica inicial de citomegalovirus sobre la eficacia del tratamiento anticipado con ganciclovir en receptores de trasplante de progenitores hematopoyéticos

To study the impact of initial cytomegalovirus (CMV) viral load on virological response to ganciclovir preemptive therapy in allogeneic stem cell transplant (SCT) recipients after 4 weeks of treatment. Eighty-one consecutive allogeneic SCT recipients were included. Preemptive therapy was initiated when CMV load was positive for 2 consecutive weeks or when a viral load >5000copies/mL was detected in 1 sample. If viral load was >400copies/mL after 2 weeks of treatment, maintenance treatment with ganciclovir was continued for 2 additional weeks. Virological failure was defined as a CMV load >400copies/mL after 4 weeks of treatment. Ganciclovir preemptive therapy was initiated in 32 patients (39.5%) who had 39 episodes of CMV replication. Virological failure occurred in 16 patients (50%) after 18 episodes of replication (46%). Clinical failure additionally occurred in 2 episodes (5%). The only risk factor for virological failure was a peak viral load >20,000copies/mL at the beginning of treatment (OR 5.88; 95% CI: 1.49-25, P=.03). The main risk factor for CMV replication >20,000copies/mL at the start of treatment was the presence of grade II-IV acute graft-versus-host-disease (OR 16; 95% CI: 8.5-45). CMV viral load >20,000copies/mL is the main risk factor for virological failure after 4 weeks of ganciclovir preemptive therapy following SCT.