Developed Cytomegalovirus Viremia Research Articles

Predictors of cytomegalovirus reactivation after allogeneic hematopoietic cell transplantation: Insights from a real-world experience

BackgroundWe aimed to investigate factors associated with cytomegalovirus (CMV) viremia and CMV disease and its impact on post-transplant outcomes including overall survival (OS) following allogeneic hematopoietic stem cell transplantation (Allo-SCT). MethodsWe conducted a single-center retrospective study including 452 Allo-SCT recipients (matched unrelated donor, MUD 61%; haploidentical, haplo 39%) from 2016 to 2021. Data were analyzed using SPSS v28. Descriptive (chi-square and t-test), Kaplan-Meier and regression analyses were conducted. ResultsThe median age was 57 years. Sixty-one percent were males and 84.3% were Caucasians. CMV serostatus was positive in 59.1% of recipients. The median follow-up was 24.4 months. CMV viremia and CMV disease were observed in 181 (40%) and 32 (7%) patients, respectively. Among CMV seropositive recipients, 65% developed CMV viremia and 11% were noted to have CMV disease compared to 4% and 1% in seronegative recipients, respectively (p < 0.001). Patients with CMV disease had significantly lower OS than those without CMV disease (median 14.1 months vs. not reached, p = 0.024); however, OS was not associated with CMV viremia (median not reached in both groups, p = 0.640). Letermovir prophylaxis was used in 66% (n = 176/267) of CMV seropositive recipients, but no impact was observed on the incidence of CMV viremia or CMV disease and OS. ConclusionsCMV disease leads to significantly inferior survival after an allogeneic hematopoietic cell transplantation. Recipient CMV seropositive status was associated with the risk of CMV viremia and CMV disease, and this was not abrogated with the use of Letermovir prophylaxis.

Comparison of valganciclovir versus foscarnet for the treatment of cytomegalovirus viremia in adult acute leukemia patients after allogeneic hematopoietic cell transplantation

Cytomegalovirus (CMV) reactivation increases treatment-related mortality (TRM) after allogeneic hematopoietic cell transplantation (allo-HCT). We analyzed 141 adult acute leukemia (AL) patients suffered allo-HCT between 2017 and 2021, who developed CMV viremia post-HCT and treated with valganciclovir or foscarnet, to evaluate effectiveness and safety of both drugs. Viremia clearance rates (14 and 21 d post treatment) and toxicities were similar in two groups. However, valganciclovir was associated with a lower cumulative incidence of CMV recurrence within 180 days (16.7% vs. 35.7%, p=0.029) post CMV clearance. Finally, 2-year TRM was lower in valganciclovir group (9.7% ± 0.2% vs. 26.2% ± 0.3%, p = 0.026), result a superior 2-year overall survival (OS; 88.1% ± 5.2% vs. 64.4% ± 5.5%, p = 0.005) and leukemia-free survival (LFS; 82.0% ± 5.9% vs. 58.9% ± 5.6%, p = 0.009). Valganciclovir might decrease CMV viremia recurrence and led to better long-term outcome than foscarnet in adult AL patients developed CMV viremia post-HCT. Considering the inherent biases of retrospective study, well-designed trials are warranted to validate our conclusion.

A Real-World Efficacy of Letermovir Primary Prophylaxis for Cytomegalovirus Infection after Allogeneic Hematopoietic Stem Cell Transplantation in China: A Single-Center Retrospective Analysis

Introduction: Cytomegalovirus (CMV) infection is a common complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT) and is associated with increased mortality. Letermovir (LET) is a novel antiviral drug used to prevent CMV infection. Methods: We retrospectively analyzed 167 consecutive patients who underwent allo-HSCT between August 2022 and May 2023, who received LET 240 mg/day, to evaluate the efficacy and safety of LET in primary prophylaxis for clinically significant CMV infection (csCMVi), defined as CMV disease or CMV viremia reactivation, in real-world situations in China. Results: Among the enrolled 167 patients, 95.21% (159/167) of patients underwent a haploidentical donor (HID) transplant and 4.79% (8/167) a matched unrelated donor (MUD) transplant. 96.41% of the recipients were CMV seropositive, and only 6 recipients were CMV seronegative but donor seropositive. The median interval from allo-HSCT to the administration of LET was 7 (2-55) days. A total of 121 patients received LET within 14 days after HSCT. With the median follow-up 162(74-397) days post-HSCT, the incidence of CMV viremia was 11.98% (20/167). 3 patients developed CMV viremia after discontinuation of LET medication. Among the 20 patients with CMV viremia, the median duration of preemptive therapy was 9 (3-28) days, and the peak level of CMV-DNA was 1867 (1228-22383) copies/ml. Only 1 patient developed refractory CMV viremia with prolonged preemptive anti-CMV treatment. No patients were diagnosed with clinically significant CMV disease. Patients who developed CMV viremia or not were similar with respect to the CMV IgG status of the recipient at HSCT, donor CMV IgG, and GVHD incidence. Notably, the CMV viremia incidences of patients who received LET within 14 days and after 14 days post-HSCT were 7.44% and 23.91%, respectively (p=0.005). The incidence of EBV viremia was 17.16% (29/169), and 9 developed PTLD. The six-month overall survival was 93.4±2.1% in all patients who received LET prophylaxis. Meanwhile, LET prophylaxis was well tolerated. No drug-related death or permanent discontinuation was reported due to toxicity. Conclusion: Letermovir was effective and safty as primary prophylaxis of csCMVi, particularly initiating early post-HSCT.

Risk Factors Associated with Survival Following Ganciclovir Prophylaxis through Day +100 in Cytomegalovirus At-Risk Pediatric Allogeneic Stem Cell Transplantation Recipients: Development of Cytomegalovirus Viremia Associated with Significantly Decreased 1-Year Survival

Cytomegalovirus (CMV) reactivation is a major cause of morbidity and nonrelapse mortality (NRM) in pediatric allogeneic stem cell transplantation (alloSCT) recipients. Approximately 80% of CMV seropositive alloHCT recipients will experience CMV reactivation without prophylaxis. The impacts of ganciclovir prophylaxis and subsequent CMV viremia on 1-year survival and 1-year NRM are unknown. The primary objective of this study was to determine the effect of CMV viremia on the probability of 1-year survival and 1-year NRM in pediatric alloSCT recipients receiving 100 days of ganciclovir prophylaxis. The secondary objective was to determine the effect of other risk factors on 1-year survival and 1-year NRM. All patients age 0 to 26 years who underwent alloSCT between June 2011 and May 2020 and received ganciclovir prophylaxis for 100 days at Westchester Medical Center, an academic medical center, were analyzed. Ganciclovir was administered to at-risk alloSCT recipients (donor and or recipient CMV+ serostatus) as 5 mg/kg every 12 hours from the first day of conditioning through day -1 (recipient CMV+ only) followed by 6 mg/kg every 24 hours on Monday through Friday beginning on the day of an absolute neutrophil count >750/mm3 and continuing through day +100. National Cancer Institute Common Terminology Criteria for Adverse Events 5.0 criteria were used to grade toxicity. NRM was analyzed using competing survival analysis with relapse death as a competing event. The log-rank and Gray tests were performed to compare the 1-year survival probabilities and NRM cumulative incidence between patients who experienced CMV viremia post-alloSCT and those who did not. Univariate Cox regression analysis was performed for the following risk factors: CMV viremia, donor source, sex, malignant disease, disease risk index, conditioning intensity, receipt of rabbit antithymocyte globulin (rATG)/alemtuzumab, graft-versus-host disease (GVHD) prophylaxis, CMV donor/recipient serostatus, grade II-IV acute GVHD, and grade 3/4 neutropenia necessitating discontinuation of ganciclovir, treating the last 3 factors as time-dependent covariates. Those with P values < .2 were included in the multivariate Cox regression analysis. Eighty-four alloSCT recipients (41 males, 43 females; median age, 10.8 years [range, .4 to 24.4 years]) were analyzed. Multivariate analysis showed significantly lower 1-year survival and significantly higher 1-year NRM in patients who developed CMV viremia compared to those who did not (P=.0036). No other risk factors were significantly associated with 1-year survival or 1-year NRM. One-year survival was significantly decreased and 1-year NRM was significantly increased in pediatric alloSCT recipients who developed CMV viremia following ganciclovir prophylaxis. No other risk factors were found to be associated with 1-year survival or 1-year NRM. Alternative CMV prophylaxis regimens that reduce CMV viremia should be investigated in pediatric alloSCT recipients at risk for CMV infection.

The Association of pDC Dose in Graft with CMV and EBV Infection after Allo-HSCT in Pediatric Patients: A Single-Center Experience

Introduction: Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infection remains one of the most important complications that potentially causes non-relapse mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Plasmacytoid dendritic cells (pDC) are a sentinel cell type with potent capacity of recognizing viral antigens and producing massive type I interferon, which contributes to the effective elimination of viral infection. The association of pDC in allogeneic grafts (allo-grafts) with CMV and EBV infection is widely unknown. Here we aim to investigate the association of pDC dose infused with CMV and EBV infection within 100 days after HSCT. Methods: A total of 100 patients receiving allo-HSCT at the Children's Hospital of Soochow University were included. A cohort of 80 patients was enrolled from September 2020 to June 2021 (discovery cohort); another cohort of 8 patients was enrolled from July 202 to August 2022 (validation cohort). Conditioning regimens based on busulfan/cyclophosphamide (Bu/Cy) included myeloablative, reduced intensity and non-myeloablative conditioning. Copies of viral genomes in peripheral blood were detected weekly after HSCT using real-time quantitative polymerase chain reaction. Patients who tested positive for CMV viremia were given ganciclovir as preemptive therapy, while patients with EBV viremia were treated with upfront rituximab. Samples of allogeneic grafts (allo-grafts) from corresponding donors were collected to examine DC subsets and T-cell subsets by flow cytometry. The discovery cohort was analyzed to investigate the association of pDC dose infused with CMV and EBV infection within 100 days after HSCT; the validation cohort was analyzed to verify this association and investigate its correlation with pDC reconstitution by testing patients’ circulating pDC concentration on day +30 after HSCT. Results: At baseline, mean age of discovery cohort was 8 years (range, 1-15 years); the diagnosis included acute myeloid leukemia (AML) (n=22, 28%), myelodysplastic syndrome (MDS) (n=4, 5%), acute lymphoblastic leukemia (ALL) (n=24, 30%), aplastic anemia (n=20, 25%), and other diagnosis (n=10, 12%) requiring HSCT. Within 100 days after HSCT, 54 patients (68%) developed CMV viremia at a median of 28.5 days (range, 13-65 days); multivariate analysis suggested that the high pDC dose infused was an independent protective factor for CMV viremia (HR, 0.456; 95% CI, 0.247-0.843; p = 0.012). Within 100 days after HSCT, 41 patients (51%) developed EBV viremia at a median of 24 days (range, 11-90); multivariate analysis suggested that the high dose of pDC infused was an independent protective factor for EBV viremia (HR, 0.499; 95% CI, 0.257-0.967; p = 0.040). In the validation cohort, patients developing CMV and EBV viremia within 100 days after HSCT had significantly lower pDC dose in graft compared to patients without CMV and EBV viremia. On day +30 after HSCT, circulating pDC concentration was higher in patients without CMV and EBV viremia than those who developed viremia. Additionally, patients with a higher pDC dose infused had a correlation with a higher circulating pDC concentration on day +30 after HSCT (r = 0.68). Conclusions: In this retrospective study, we observed that pDC dose infused might be a protective factor for CMV and EBV infection early after HSCT. In addition to the inherent ability to produce antiviral immune responses, a high pDC dose may lower the risk of viral infection by enhancing pDC reconstitution early after HSCT.

Invasive Cytomegalovirus Disease in a Low Risk CMV Serostatus, D-/R- Lung Transplant Recipient

<h3>Introduction</h3> Cytomegalovirus (CMV) infection is a major cause of morbidity and mortality among transplant patients. Here, we report a case of lung transplant patient with low risk CMV serostatus (D-/R-) who developed invasive CMV disease. <h3>Case Report</h3> A 64-year-old lady with COPD underwent bilateral lung transplant. CMV serostatus was donor IgG negative / recipient IgG negative. Basiliximab was used for induction and was maintained on tacrolimus, mycophenolate and prednisone. Intraoperatively, she received 2 leucoreduced PRBC's. 15 days post-transplant she developed CMV viremia and was started on treatment dose valganciclovir. No mutations noted on the resistance panel. 2 weeks on therapy, there was no reduction in the CMV PCR. Chest CT showed a right pleural effusion which was exudative in nature. Microbiology testing was negative. Fluid cytology showed CMV cytopathic changes. Valganciclovir was changed to iv ganciclovir because of her GI absorption concerns. With 6 weeks of iv ganciclovir and monthly CMV Immune globulin, CMV PCR log values steadily declined. <h3>Summary</h3> Lung transplant patients with low risk CMV serostatus can have a minor risk of transfusion acquired (TA) or community acquired (CA) CMV infection. A single center retrospective study of low-risk organ transplant patients did not identify any cases of TA CMV infection in patients receiving leucoreduced PRBC. Another study showed 2.4% risk of TA CMV infection in patients receiving non-leucoreduced PRBC. CA CMV risk is greater than TA CMV, with the incidence being higher in children (3/100 patient years) compared to adults (0.46/100 patient years). Currently no guidelines exist to recommend CMV prophylaxis in low risk CMV serostatus transplant patients. Hence measures need to be taken to monitor such patients who are at increased risk for TA or CA CMV. Recipients whose IgG was negative during transplant work up should be retested at the time of transplant. CMV PCR monitoring should be considered if the donor or recipient received extensive transfusions.

The addition of adjunctive letermovir to valganciclovir for refractory cytomegalovirus viremia in kidney transplant recipients.

Persistent viral replication resulting in ongoing cytomegalovirus (CMV) viremia despite adequate therapy is difficult to manage and associated with negative outcomes. We report a case series of kidney transplant recipients receiving adjunctive letermovir in combination with valganciclovir for refractory CMV. Adult patients receiving a kidney or kidney-pancreas transplant were included if they developed CMV viremia and initiated letermovir 480mg daily as part of a dual therapy regimen with valganciclovir 900mg twice daily between 1/9/2020 and 31/12/2020. Included patients received ≥90 days of valganciclovir and had a detectable viral load less than 1000 Iu/ml (log10 <3) at the time of letermovir initiation. The primary objective was to evaluate the impact of adjunctive letermovir on viral clearance to negativity. We also evaluated effect of letermovir on tacrolimus levels. Eight patients were included. Letermovir was added 223 ± 105 days after initiation of CMV treatment with ganciclovir derivatives. Median viral load at initiation was 139.7 (range: 73-355) IU/ml and did not clear or change significantly after 2, 4 and 12weeks of adjunctive letermovir (132.5 [range: 34.5-513] IU/ml vs. 68.7 [range: 34.5-574] IU/ml vs. 78.3 [range: 34.5-347] IU/ml, p>0.05). Tacrolimus was reduced by ∼30% in anticipation of a letermovir-tacrolimus drug interaction. Despite this reduction, mean tacrolimus serum levels two weeks after adjunctive letermovir increased by 43% (5.6 ± 1.6ng/ml vs 8.0 ± 4.6ng/ml). In kidney and kidney-pancreas recipients with refractory CMV, the use of adjunctive letermovir did not result in viral clearance. Additionally, despite a mean tacrolimus dose reduction of 30% at letermovir initiation, serum concentrations increased by over 40%. Further investigation into the optimal approach to refractory CMV is needed.

Efficacy of low-dose valganciclovir in Cytomegalovirus R+ lung transplant recipients: a retrospective comparative analysis

BackgroundCytomegalovirus (CMV) infection is extremely common after lung transplant and can be associated with significant morbidity and mortality. Current practice suggests the use of 900 mg daily of valganciclovir for CMV prophylaxis, but there is no literature assessing whether 450 mg daily of valganciclovir is sufficient in intermediate CMV risk lung transplant recipients. Therefore, we sought to assess the role of low-dose valganciclovir (LDV) versus high-dose valganciclovir (HDV) prophylaxis in intermediate-risk (R+) recipients.MethodsWe conducted a retrospective analysis on lung transplant recipients at the Norton Thoracic Institute in Phoenix, Arizona looking at intermediate-risk patients that received either valganciclovir 450 mg per day (LDV) or 900 mg/day (HDV). All patients were followed for 1 year post-transplant for incidence of CMV viremia. The primary outcome was the rate of CMV viremia as determined by a positive CMV polymerase chain reaction ([PCR] >2.7 log copies/mL). Secondary outcomes included rate of adverse events, acute cellular rejection, and mortality.ResultsThe primary analysis included 103 patients (55 in the LDV group, 48 in the HDV group). In the LDV group, 9 patients (16.4%) developed CMV viremia compared to 4 (8.3%) in the HDV group (p=0.221) with no difference observed in adverse event rates between groups.ConclusionThere was no statistical difference between groups for the primary outcome. However, the effect size demonstrated in this analysis may be of clinical relevance and valganciclovir 450 mg daily would not be recommended in intermediate risk lung transplant recipients at this time. To confirm our results, further prospective studies enrolling larger patient populations are necessary.

1702. Assessing the Safety and Efficacy of Valganciclovir Dosing for Cytomegalovirus Prophylaxis in Solid Organ Transplant Recipients on Hemodialysis

BackgroundValganciclovir is the standard of care used for the prevention of Cytomegalovirus (CMV) infections among solid organ transplant (SOT) recipients. Currently there is minimal guidance for prophylaxis in SOT recipients undergoing intermittent hemodialysis (IHD). At Mount Sinai Hospital (MSH), the current practice for CMV prophylaxis in SOT recipients on IHD is valganciclovir 450 mg every other day (Q48H) or three-times weekly (TIW). This study aims to evaluate the safety and effectiveness of these dosing regimens in SOT recipients on IHD.MethodsA single-center, retrospective chart review study was conducted among all MSH SOT recipients on valganciclovir 450 mg Q48H or TIW for CMV prophylaxis and undergoing IHD for at least 30 days. The primary study outcome was the safety of using these valganciclovir doses determined by the incidence of leukopenia, thrombocytopenia, and the administration of growth colony stimulating factor (GCSF). The secondary outcome were the incidences of CMV viremia and CMV disease while on prophylaxis.ResultsEighteen transplant encounters satisfied the inclusion and exclusion criteria. The majority were liver (7, 38.9%) and kidney (5, 27.8%) transplants. Thirteen (72.2%) recipients were on valganciclovir 450 mg Q48H dosing, while 5 (27.8%) were on valganciclovir 450 mg TIW dosing. Both the mean platelet count nadir (131 ± 93 vs 161 ± 115) and mean white blood cell count nadir (3.4 ± 2.5 vs 5.1 ± 3.8) were lower in the Q48H regimen. Four patients (22.2%) in the Q48H regimen group required GCSF vs none (0.0%) in the TIW regimen. No patient had a detectable CMV viral load while on either prophylactic dose. Two (11.1%) CMV high risk patients on the every other day dosing regimen and one (5.6%) CMV moderate risk patient on the three times weekly regimen developed CMV viremia about 2-3 months after their prophylaxis was stopped.Table 1. Baseline Demographics. Table 2. Primary Outcomes Table 3. Secondary Outcomes ConclusionValganciclovir 450 mg TIW may be safer than and as efficacious as Q48H dosing for prophylaxis in SOT recipients on chronic IHD. This data supports the use of three times weekly dosing as standardized practice at MSH, however more data is necessary to determine a conclusive result.Disclosures All Authors: No reported disclosures

Extended letermovir administration, beyond day 100, is effective for CMV prophylaxis in patients with graft versus host disease.

Cytomegalovirus (CMV) reactivation is associated with significant morbidity and mortality after an allogeneic hematopoietic cell transplant (AHCT), and graft versus host disease (GVHD) increases the risk of CMV reactivation. Letermovir is approved for CMV prophylaxis in CMV-seropositive patients, but has only been studied through day 100 post-transplantation in the registration trial. Its efficacy in preventing CMV in patients with GVHD requiring treatment beyond the day 100 milestone has not been studied. We retrospectively analyzed all patients who underwent an AHCT at a single center over a period of 24months, and identified a cohort of 20 patients who received extended duration of letermovir (beyond 100days) after the diagnosis of GVHD. The primary end point was the incidence of clinically significant CMV infection, defined as onset of CMV disease or initiation of preemptive therapy with alternative antiviral agents. In this high-risk cohort, only one patient (5%) developed a clinically significant CMV infection, requiring preemptive therapy. No patients developed CMV organ disease. Three additional patients developed CMV viremia of≥150IU/mL while on letermovir and after the onset of GVHD, and none required additional treatment. Receipt of post-transplant cyclophosphamide (PTCy) and low CD4 count after the development of GVHD were associated with breakthrough CMV viremia while on extended duration letermovir. Extended duration letermovir was efficacious in preventing clinically significant CMV infections in patients with GVHD.

CMV Viremia after Discontinuation of Valganciclovir Prophylaxis in Lung Transplant Recipients

Cytomegalovirus (CMV) remains a significant cause of acute morbidity following lung transplantation, and has been linked to the early onset of chronic allograft rejection. Most lung transplant centers utilize prophylaxis with valganciclovir (VGC) to prevent CMV infection. Long-term VGC therapy can be complicated by adverse side effects that include myelosuppression, leading to early discontinuation. We hypothesize that the risk of CMV infection following withdrawal of VGC will be affected by the D/R serology status. We performed a single center, retrospective study of patients who received a lung transplant between January 1st, 2016 to December 31st, 2018. Patient information included gender; VGC discontinuation due to myelosuppression; time from transplant to VGC discontinuation; and time from VGC discontinuation to first detectable CMV PCR. A total of 112 patients received a lung transplant during the study period (table 1). All patients initiated VGC after transplant. CMV D+/R- patients also received CMV immunoglobulin every 2 weeks for 7 doses. 40 patients (36%) developed CMV viremia, with more than half of these cases occurring in CMV+/- recipients. All but two of these cases occurred following discontinuation of VGC. None of the cases of viremia were associated with end-organ disease. Although recent data suggests that extending VGC prophylaxis up to 18 months in lung transplant patients may offer additional protection, the side effects may limit this practice. Incidence of CMV viremia following discontinuation was highest in D+/R- patients and in patients who discontinued therapy early, but there were no patients with end organ disease. These results support a VGC prophylaxis strategy where duration of therapy is based on D/R serologies coupled with weekly monitoring of CMV PCR for 16 weeks after VGC discontinuation.

Impact of CMV Reactivation, Treatment Approaches, and Immune Reconstitution in a Nonmyeloablative Tolerance Induction Protocol in Cynomolgus Macaques

Cytomegalovirus (CMV) infection is a serious complication in immunosuppressed patients, specifically transplant recipients. Here, we describe the development and use of an assay to monitor the incidence and treatment of CMV viremia in a Cynomolgus macaque model of bone marrow transplantation (BMT) for tolerance induction. We address the correlation between the course of viremia and immune reconstitution. Twenty-one animals received a nonmyeloablative conditioning regimen. Seven received cyclosporine A for 28 days and 14 received rapamycin. A CMV polymerase chain reaction assay was developed and run twice per week to monitor viremia. Nineteen recipients were CMV seropositive before BMT. Immune reconstitution was monitored through flow cytometry and CMV viremia was tracked via quantitative polymerase chain reaction. Recipients developed CMV viremia during the first month post-BMT. Two animals developed uncontrollable CMV disease. CMV reactivation occurred earlier in cyclosporine A-treated animals compared with those receiving rapamycin. Post-BMT, T-cell counts remained significantly lower compared with pretransplant levels until CMV reactivation, at which point they increased during the viremic phase and approached pretransplant levels 3 months post-BMT. Management of CMV required treatment before viremia reached 10 000 copies/mL; otherwise clinical symptoms were observed. High doses of ganciclovir resolved the viremia, which could subsequently be controlled with valganciclovir. We developed an assay to monitor CMV in Cynomolgus macaques. CMV reactivation occurred in 100% of seropositive animals in this model. Rapamycin delayed CMV reactivation and ganciclovir treatment was effective at high doses. As in humans, CD8 T cells proliferated during CMV viremia.

Safety of Cytomegalovirus Prophylaxis on Engraftment in Pediatric Umbilical Cord Blood Transplant Following Reduced Intensity Conditioning

Background Reduced intensity conditioning (RIC) transplant carries the advantage of decreased transplant related morbidity and mortality, however comes with an increased risk of viral infections, particularly cytomegalovirus (CMV) in the setting of serotherapy and umbilical cord blood (UCB) grafts. Given this, the use of prophylaxis is considered, though with hesitation given associated myelosuppression and nephrotoxicity. We report outcomes of CMV prophylaxis with ganciclovir and foscarnet on engraftment and viremia in the setting of RIC umbilical cord blood transplant (UCBT). Methods A retrospective chart review was conducted reviewing patients with non-malignant disease who underwent UCBT on an institutional protocol between 2016 - 2019. A RIC regimen was administered using alemtuzumab (Day -14), hydroyxurea (Day -14 to -5), fludarabine (Day -9 to -5), melphalan (split Day -4 & -3), and thiotepa (Day -2). ClinicalTrials.gov: NCT01962415. The patients were divided into 3 groups: patients who did not receive CMV prophylaxis (Group 1), patients who did (Group 2), and patients who received preemptive treatment prior to Day 0 due to CMV DNAemia (Group 3). CMV prophylaxis included ganciclovir 5 mg/kg/d (Day -10 to -2) followed by foscarnet 90 mg/kg daily (from Day +1) to reduce marrow suppression. Results Group 1 included 14 patients. Neutrophil engraftment occurred in all patients [median: 16 days; range: 11 – 33]. Platelet engraftment (> 50k) occurred at a median of 45.5 days (range: 33 – 79). Of the 14 patients, 1 patient received acyclovir as CMV prophylaxis while the remaining 13 received ganciclovir/foscarnet. 5 developed CMV viremia (max copies of 95,000 IU/mL); one of whom had graft rejection attributed to CMV. These patients were treated preemptively following detection of DNAemia. Group 2 included 6 patients. Neutrophil engraftment occurred in all patients [median: 15 days; range: 13 – 18]. Platelet engraftment occurred at a median of 32 days (range: 26 – 39). 5 patients developed CMV viremia (max copies of 3290 IU/mL). Similar to Group 1, these patients were also escalated to treatment doses of ganciclovir and switched to foscarnet and/or human CMV immune globulin (CytoGAM) with treatment failure. Group 3 included 2 patients who were found to have CMV DNAemia prior to Day 0 therefore received preemptive treatment. Neutrophil and platelet engraftment occurred at a median of 14 and 42 days, respectively. In all groups, no patient developed end-organ disease. Conclusion In our single-institution pediatric UCB transplant dataset, there is no suggestion that pre-engraftment exposure to CMV prophylaxis with ganciclovir and foscarnet impacted the kinetics of either neutrophil or platelet engraftment. Therefore, CMV prophylaxis in seropositive patients undergoing UCB transplant could be considered alongside preemptive therapy as an option for management of viral reactivation.

Clinical Determinants of T-Cell Receptor Diversity after Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia

T-cell reconstitution after allogeneic haematopoietic stem cell transplantation (alloSCT) is critical for protection against infection and to mediate the graft versus leukemia (GVL) effect against hematological malignancies including acute myeloid leukemia (AML). T-cell reconstitution post-alloSCT is significantly impacted by exogenous factors including T-cell depleting strategies, immunosuppressive medications and the prohibitive effects of graft versus host disease (GVHD) and infection. The early T-cell repertoire post-alloSCT is oligoclonal and clinical events such as infection and GVHD may adversely impact recovery of a diverse TCR repertoire. The objectives of this study were to investigate clinical determinants of TCR diversity at day 100 after alloSCT and the impact of TCR diversity on risk of early AML relapse after alloSCT. Methods Twenty-nine patients who underwent HLA-matched sibling or unrelated donor alloSCT were included in this cohort comprising 16 patients with AML relapse at day 100 to 180 post-alloSCT and 13 control patients who did not relapse post-alloSCT. All patients received unmanipulated peripheral blood or bone marrow stem cells. Anti-thymocyte globulin was administered to all patients receiving unrelated donor stem cells as per institutional practice. Surveillance for cytomegalovirus (CMV) viremia in peripheral blood (plasma) was monitored twice weekly using polymerase chain reaction (PCR) and pre-emptive therapy with intravenous ganciclovir or oral valganciclovir was commenced in patients with plasma viral load of 400 copies/mL or greater. Peripheral blood samples were obtained at day 100 (early time-point). Eleven patients had follow-up samples 1-2 years post-transplant (late time-point). T-cells were isolated using immunomagnetic separation. Following DNA extraction, TCRβ loci deep amplicon sequencing was performed using LymphoTrack TRB. Sequence assembly, annotation and error correction was performed by MiXCR. TCR diversity was quantified using inverse Simpson's diversity index (1/D). Results TCRβ sequencing of the entire cohort of 29 patients was performed with a mean of 454516 sequence reads per patient. Median time from transplant for the early post-alloSCT timepoint was 99 days. Median TCR repertoire diversity (1/D) early post-transplant was 104.3 (IQR 46.5-398.4). TCR diversity was significantly greater in patients who received T-cell replete transplants from matched sibling donors compared with T-cell depleted transplants from unrelated donors (siblings 130.1 [IQR 54-1017] vs unrelated donors 64 [IQR 28.9-96.9]; P=0.04). Early TCR diversity was significantly reduced in recipients who were CMV seropositive prior to transplant compared with seronegative patients (77.5 [IQR 42.4-127.5] vs 718.8 [IQR 75.5-1884]; P=0.01). Twenty patients (69%) developed CMV viremia, defined as any detectable CMV virus in peripheral blood, prior to day 100 post-alloSCT. Early TCR diversity was significantly reduced in patients with CMV viremia within the first 100 days post-alloSCT (83.5 [IQR 42.4-131.5] vs 964.4 [IQR 71.7-2399]; P=0.02). There was no significant difference in TCR diversity at day 100 in patients who had prior acute GVHD compared to those who did not. There was no significant difference in early TCR diversity at the time of AML relapse compared with patients who remained in remission (78.4 [IQR 38-799.2] vs 132.8 [IQR 59.5-753.6]; P=0.22), suggesting that a restricted TCR repertoire early post-transplant is not a mechanism of AML relapse. Eleven patients had serial samples analysed at early (day 100) and late (between 1-2 years post-transplant) timepoints. All patients remained free of leukemia relapse between these two timepoints. Patients with early CMV viremia (prior to day 100) continued to have a significantly reduced TCR diversity late post-transplant compared with patients who did not have early CMV reactivation (33.2 [IQR 27.3-61.4] vs 3868 [IQR 1421-4565]; P=0.006), indicating that early CMV viremia had a persistent effect on post-transplant T-cell recovery extending to 1-2 years post-transplant. Conclusion T-cell depletion and CMV viremia are key determinants of early TCR repertoire diversity post-alloSCT. CMV viremia has persistent and deleterious effects on TCR repertoire late post-transplant. TCR diversity does not impact early AML relapse post-alloSCT. Disclosures Ritchie: Amgen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy; BMS: Research Funding; Takeda: Research Funding; Beigene: Research Funding; Imago: Research Funding; Novartis: Honoraria; Sanofi: Honoraria. Koldej:NanoString Technologies: Other: Travel grant. Blombery:Novartis: Consultancy; Janssen: Honoraria; Invivoscribe: Honoraria.

1747. Impact of Inappropriately Low Cytomegalovirus (CMV) Prophylaxis Dosing on CMV Outcomes Among Lung Transplant (LT) Recipients

BackgroundValganciclovir (VGCV) and ganciclovir (GCV) are commonly used to prevent CMV in at-risk lung transplant recipients (LTRs). Because renal function changes frequently in the post-transplant setting, antiviral under-dosing may occur. We sought to determine the frequency of GCV/VGCV under-dosing and its impact on CMV-related outcomes among LTRs.MethodsWe conducted a retrospective cohort study of all adult LTRs with a CMV seropositive donor (D+) between 2014 and 2016 at the Hospital of the University of Pennsylvania. Exposed patients were those with exposure to inappropriately low-dose GCV/VGCV. Unexposed patients were those whose antiviral dosing was consistently appropriate for their creatinine clearance. We employed a multivariable Cox proportional hazard analysis to determine the impact of low-dose prophylaxis on time to CMV infection post-transplant; prophylaxis dosing was incorporated as a time-varying covariate in this survival analysis.Results108 adults underwent CMV D+ LT during the study period. 46 (43%) experienced low prophylaxis dosing at some point during their prophylaxis course. 47 (43%) LTRs developed CMV viremia, of which 10 (9%) were still on prophylaxis. 20 (19%) LTRs developed CMV disease and 6 (6%) had ganciclovir-resistant CMV. In the multivariable Cox analysis, we found that there was not a significant association between exposure to any low-dose prophylaxis and the hazard of CMV infection (HR = 1.001, 95% CI 0.99–1.01, P = 0.75; Table 1), even among CMV seronegative recipients (D+/R−) (HR = 1.002, 95% CI 0.99–1.01, P = 0.68). When only those who received > 28 days of low-dose prophylaxis (N = 6, 6%) were evaluated, there was a trend toward an increased hazard of CMV infection (HR = 1.001, 95% CI 0.999–1.004, P = 0.18; Table 2).ConclusionCMV D+ LTR are frequently exposed to inappropriately low CMV prophylaxis dosing. This does not appear to significantly increase the risk for CMV infection, though prolonged subtherapeutic exposure merits further exploration as a risk factor for CMV outcomes in higher-risk patients. Disclosures All authors: No reported disclosures.

A case of severe nephrotic syndrome caused by isolated CMV glomerulopathy with ganciclovir resistant UL 97 mutation

Introduction: While many cases of cytomegalovirus (CMV) nephropathy have been reported in the literature, isolated CMV glomerulopathy is considered a rare finding. Case Presentation: We report the case of a CMV-negative recipient of kidney allograft from a CMVpositive donor (D+/R-), the recipient subsequently developed severe nephrotic syndrome secondary to biopsy-proven isolated CMV glomerulopathy. Conclusion: The patient developed CMV viremia with ganciclovir resistant UL97 mutation. His treatment course was resistant to recommended dose of intravenous ganciclovir, so therapy was changed to foscarnet with resolution of his viremia and reduction in proteinuria.

Does the Use of Serum Ganciclovir Levels to Adjust Valganciclovir Dosing Prevent the Development of CMV Resistance in CMV Mismatched Heart Transplant Recipients? The Mid America Experience

Purpose Cytomegalovirus (CMV) infection can lead to devastating sequelae post heart transplant (HTx), such as organ invasive disease, rejection and coronary allograft vasculopathy. CMV naive HTx patients (pts) who receive organs from CMV positive donors are at very high risk for CMV-related complications. The standard prophylaxis is renally-dosed valganciclovir (VAL) for 12 months, but this one-size-fits-all approach may lead to inadequate serum ganciclovir (GCV) levels, predisposing the pts to VAL resistance. Methods We conducted a retrospective chart review of HTx pts who were CMV recipient negative/donor positive from 12/15-9/18. We started using serum trough GCV levels to guide VAL dosing in 6/17, aiming for trough level of 0.35-0.7 mcg/mL. Pts followed before protocol implementation were in group A and pts who had GCV levels drawn proactively any time during their first year post HTx were in group B. GCV trough levels were checked at 2 weeks, 3 and 6 months, as well as 2 weeks after GCV dose adjustment. CMV viremia was defined as ≥ 137 IU/mL. Results This retrospective study included 29 pts (5 women, mean age 56.3±12.4 years). Group A had 8 pts and group B had 21 pts. 5 pts in group A developed CMV viremia, and 3 developed VAL resistance, requiring treatment with cidofovir or foscarnet. For group B pts, GCV levels ranged from 0.1 to 1.9 mcg/mL. 10 pts achieved therapeutic GCV levels on standard VAL dosing. The other pts required VAL dosing adjustments in increments of 450 mg (maximum 1350 mg/day). 5 pts with levels higher than 0.9 mcg/mL developed leukopenia and VAL dose was adjusted. 3 group B pts developed CMV viremia prior to establishing goal GCV trough levels but none developed CMV resistance. At the end of year 1, CMV IgG was tested, and VAL continued until seroconversion occurred. One pt who remained CMV IgG negative developed viremia when VAL was inadvertently discontinued at 1 year. Conclusion Given the increasing frequency of CMV resistance in HTx pts, we began using trough GCV level-guided VAL dosing instead of standard dosing in 6/17. Our initial experience showed 3/8 seronegative pts developed VAL resistance using standard dosing, whereas 0/21 pts developed VAL resistance using GCV level to adjust VAL dosing. These encouraging findings will warrant a larger experience for confirmation.

Cytomegalovirus Reactivation in Children with Hemoglobinopathies Who Undergo Hematopoietic Cell Transplantation with Distal Alemtuzumab

Introduction Cytomegalovirus (CMV) viremia after allogeneic hematopoietic cell transplant (HCT) is associated with substantial morbidity. In vivo T cell depletion with alemtuzumab is a known risk factor for CMV reactivation. After observing very early CMV viremia in patients who received distal alemutuzumab in preparation for HCT for hemoglobinopathies, we implemented a quality improvement project to decrease the burden of CMV in this population. Objective To describe patterns of CMV reactivation before and after changing our CMV prophylaxis and surveillance strategies. Methods We reviewed medical records of children undergoing HCT for sickle cell disease (SCD) or beta thalassemia at Children`s Hospital of Philadelphia between 2007-2018, who received distal alemtuzumab containing conditioning regimens. Patients received alemtuzumab (48 mg, starting ∼22 days before transplant) with fludarabine and melphalan. Beginning in February 2014, CMV seropositive (CMV+) patients received prophylaxis with valganciclovir from completion of alemtuzumab through day -1 and foscarnet starting on day 0, as well as weekly CMV surveillance beginning with alemtuzumab administration. Rates of CMV reactivation, as well as balancing metrics [time to engraftment and rate of acute kidney injury (AKI) within 100 days post-HCT] were evaluated before and after implementation of this preventive approach. Results Twenty-nine children were included in the analysis. The median age was 11.1 (range: 3.1 to 17.3) years at HCT; 22 (75.9%) patients had SCD and 8 (24.1%) had beta thalassemia. All patients received bone marrow grafts, 22 (75.9%) from HLA-identical siblings and 7 (24.1%) from unrelated donors. Prior to HCT, 13 patients were CMV+. Of those, 11 (84.6%) developed CMV reactivation (7/7 pre-intervention and 4/6 post-intervention). Time from alemtuzumab start to CMV reactivation, regardless of prophylactic strategy, is shown in Figure 1. CMV reactivation occurred at a median of 4 (range: -11 to +13) days after planned HCT. During the post-intervention period, CMV reactivation was identified in 2 patients prior to the start of the proximal cytotoxic phase of conditioning and HCT was delayed until viremia cleared. One CMV seronegative patient developed CMV viremia 47 days post-HCT. Median time to engraftment was similar before and after the intervention (12.5 versus 13 days), as was the proportion of patients with AKI (3/7 versus 1/6). Conclusion In this cohort, rates of CMV viremia were high and CMV reactivation often occurred very early in the transplant course. In two cases, CMV reactivation was identified prior to transplant day, necessitating a delay in HCT. Consideration should be given to implementing a program of screening or prophylaxis beginning as early as the start of alemtuzumab administration in CMV+ patients. Further research is needed to determine the optimal prophylactic strategy.

Letermovir for Secondary Cytomegalovirus (CMV) Prophylaxis in a Pediatric Stem Cell Transplant Patient

Patients who undergo stem cell transplants are at a significant risk of infections. Cytomegalovirus (CMV) is an organism of particular concern in this population. Current treatments options for CMV include ganciclovir, valganciclovir, foscarnet, and cidofovir. These treatment options have adverse effects such as myelosuppression or nephrotoxicity, making them less than ideal as a treatment options. Increasing rates of drug resistance is another concern. The need for alternative treatment options is paramount. Many patients require secondary prophylaxis. Letermovir is a newly approved CMV DNA terminase complex inhibitor indicated for prophylaxis of CMV infection and disease in adults. Its role in secondary prophylaxis has not been clearly defined. We report the case of an 11-year old male who had undergone a 4/6 HLA-matched cord blood transplant for Fanconi Anemia. The patient developed CMV viremia that later progressed to CMV colitis and pneumonitis. He was initially treated with ganciclovir then was found to have UL97 mutation. He was then switched to foscarnet for induction therapy, to which the patient showed a good response. The patient was subsequently transitioned to cidofovir for maintenance therapy where CMV viremia recurred. Foscarnet was re-initiated with good response then transitioned to cidofovir maintenance therapy. Unfortunately, CMV viral load began to increase prompting a change to high-dose ganciclovir. Due to concerns for myelosuppression with using high-dose ganciclovir he was switched back to foscarnet. While on foscarnet the patient had nephrotoxicity and electrolyte disturbances and the decision was made to re-initiate high-dose ganciclovir. When the patient's CMV viral load was undetectable the patient was transitioned to letermovir 480 mg daily with successful suppression of CMV viral load. Letermovir has been well tolerated and the patient has experienced no adverse effects associated with it. The patient has not required further therapy for CMV viremia since starting letermovir. Letermovir prophylaxis was stopped after four months of therapy. The patient's CMV viral load began to rise after stopping for one month with the peak at 381 copies/mL. After restarting letermovir the CMV viral load became undetectable and has remained so. Letermovir could be useful in secondary prophylaxis in pediatric patients with ganciclovir-resistant CMV who are at risk of recurrences. Further investigation is warranted for the use of letermovir in the pediatric population.

A Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial of Oral Brincidofovir for Cytomegalovirus Prophylaxis in Allogeneic Hematopoietic Cell Transplantation

Cytomegalovirus (CMV) infection is a common complication of allogeneic hematopoietic cell transplantation (HCT). In this trial, we randomized adult CMV-seropositive HCT recipients without CMV viremia at screening 2:1 to receive brincidofovir or placebo until week 14 post-HCT. Randomization was stratified by center and risk of CMV infection. Patients were assessed weekly through week 15 and every third week thereafter through week 24 post-HCT. Patients who developed clinically significant CMV infection (CS-CMVi; CMV viremia requiring preemptive therapy or CMV disease) discontinued the study drug and began anti-CMV treatment. The primary endpoint was the proportion of patients with CS-CMVi through week 24 post-HCT; patients who discontinued the trial or with missing data were imputed as primary endpoint events. Between August 2013 and June 2015, 452 patients were randomized at a median of 15 days after HCT and received study drug. The proportion of patients who developed CS-CMVi or were imputed as having a primary endpoint event through week 24 was similar between brincidofovir-treated patients and placebo recipients (155 of 303 [51.2%] versus 78 of 149 [52.3%]; odds ratio, .95 [95% confidence interval, .64 to 1.41]; P = .805); fewer brincidofovir recipients developed CMV viremia through week 14 compared with placebo recipients (41.6%; P < .001). Serious adverse events were more frequent among brincidofovir recipients (57.1% versus 37.6%), driven by acute graft-versus-host disease (32.3% versus 6.0%) and diarrhea (6.9% versus 2.7%). Week 24 all-cause mortality was 15.5% among brincidofovir recipients and 10.1% among placebo recipients. Brincidofovir did not reduce CS-CMVi by week 24 post-HCT and was associated with gastrointestinal toxicity.