1750. Epidemiology of Cytomegalovirus DNAemia in Pediatric Solid-Organ Transplant Patients

Abstract Background Despite the widespread use of prevention strategies, CMV remains a common opportunistic infection in SOTR. Contemporary data regarding CMV in pediatric SOTR is limited. We sought to determine the frequency of and risk factors for CMV infection and disease in a large single-center cohort of pediatric SOTR. Methods A retrospective cohort study of patients <22 yr of age who received lung, heart, liver, kidney, or multi-organ transplants at TCH between 2014 and 2018 was completed. Universal CMV prophylaxis was used based on risk status (Figure 1). Primary outcome was CMV DNAemia (plasma level ≥ 1,000 IU/mL). Associations with CMV DNAemia were measured using Fisher exact, Kruskal–Wallis, and multivariate logistic regression. Survival analysis and time to CMV infection were assessed using Kaplan–Meier plots. Results Among 465 SOTR, 57 (12%) had CMV DNAemia ≥ 1,000 IU/mL; this included 9/52 (17%) lung, 22/155 (14%) liver, 16/125 (13%) heart, 1/9 (11%) multi-organ, and 9/124 (7%) kidney recipients. 6 (10%) SOTR had early-onset CMV reactivation while on antiviral prophylaxis. Post-prophylaxis, 48 (85%) SOTR had CMV reactivation and 3 (5%) had primary infection. Median time to DNAemia > 1,000 IU/mL was 366 days post-transplant for lung, 115 for liver, 185 for heart, and 290 for kidney (P = 0.04), reflecting differences in prophylaxis strategies. High-risk CMV status (D+/R- for heart, liver, kidney and D+ and/or R+ for lung) was associated with CMV DNAemia (P < 0.01, Figure 2). DNAemia was not associated with age at transplantation, type of organ, or induction immunosuppression. There was no difference in survival during the study follow-up period (1 – 5 years) for SOTR with vs. without DNAemia. Overall, 18/465 (4%) SOTR had CMV disease: 2 (4%) lung, 3 (2%) liver, 5 (4%) heart, 1 (11%) multi-organ, and 7 (6%) kidney recipients. 16 had CMV syndrome and 2 had tissue-invasive disease. Median (range) maximum viral loads were 35,768 IU/mL (3,239–4,807,992) for SOTR with vs. 2,605 IU/mL (1,000–112,000) for SOTR without CMV disease (P < 0.01) Conclusion This large contemporary cohort of pediatric SOTR on universal prophylaxis demonstrates low overall rates of CMV DNAemia and CMV disease. High-risk CMV status remains associated with CMV DNAemia, suggesting that further interventions targeting this group may be warranted. Disclosures Flor M. Munoz, MD, Biocryst: Grant/Research Support; CDC: Research Grant; Moderna: Other Financial or Material Support, Safety Monitoring Board Member/Chair; NIH: Research Grant; Novavax: Research Grant; UP to Date: Author and Editor - Royalties, Other Financial or Material Support.

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#76: Epidemiology of Cytomegalovirus (CMV) in Pediatric Solid-Organ Transplant Recipients (SOTR) at Texas Children’s Hospital (TCH)

Journal of the Pediatric Infectious Diseases Society ◽

10.1093/jpids/piaa170.010 ◽

2021 ◽

Vol 10 (Supplement_1) ◽

pp. S3-S4

Author(s):

K Valencia Deray ◽

K Hosek ◽

E Moulton ◽

F Munoz ◽

G Demmler-Harrison ◽

...

Keyword(s):

High Risk ◽

Organ Transplant ◽

Invasive Disease ◽

Solid Organ ◽

Transplant Recipients ◽

Cmv Infection ◽

Kidney Recipients ◽

Cmv Disease ◽

Cmv Dnaemia ◽

Cmv Status

Abstract Background Despite the widespread use of prevention strategies, CMV remains a common opportunistic infection in SOTR. Contemporary data regarding CMV in pediatric SOTR are limited. We sought to determine the frequency of and risk factors for CMV infection and disease in a large single-center cohort of pediatric SOTR. Methods A retrospective cohort study of patients <22 years of age who received lung, heart, liver, kidney, or multi-organ transplants at TCH between 2010 and 2018 was completed. Universal CMV prophylaxis was used based on risk status (Figure 1). The primary outcome was quantifiable CMV DNAemia. Associations with CMV DNAemia were measured using Fisher exact, Kruskal–Wallis, and multivariate logistic regression. Survival analysis and time to CMV infection were assessed using Kaplan–Meier plots. Results Among 788 SOTR, 132 (17%) had quantifiable CMV DNAemia; this included 20/105 (19%) lung, 69/290 (24%) liver, 28/178 (16%) heart, 2/15 (13%) multi-organ, and 13/200 (7%) kidney recipients. Fifty-one (6%) SOTR had CMV DNAemia while on antiviral prophylaxis. Post-prophylaxis, 69 (9%) SOTR had CMV reactivation and 12 (2%) had primary infection. The median time to quantifiable DNAemia for patients that developed CMV was 290 days post-transplant for lung, 162 for liver, 186 for heart, and 294 for kidney (P < 0.01), reflecting differences in prophylaxis strategies. High-risk CMV status (D+/R– for heart, liver, kidney, and D+ and/or R+ for lung) was associated with CMV DNAemia (P < 0.01). Type of organ transplanted also showed an association with CMV DNAemia (P = 0.02) with liver transplant recipients more being more likely to have a positive CMV PCR. DNAemia was not associated with age at transplantation, type of organ, or the use of induction immunosuppression. There was no difference in survival during the study follow-up period (1–9 yr) for SOTR with vs. without DNAemia (P = 0.48). Overall, 22/788 (3%) SOTR had CMV disease, 3 (3%) lung, 4 (2%) heart, 8 (3%) liver, 1 (6%) multi-organ, and 6 (3%) kidney recipients. Twenty had CMV syndrome and 2 had tissue invasive disease. Median (range) maximum viral loads were 27700 IU/mL (233-3912694) for SOTR with vs. 900 IU/mL (26-112000) for SOTR without CMV disease (P < 0.01). Conclusion This large contemporary cohort of pediatric SOTR on universal prophylaxis demonstrates low overall rates of CMV DNAemia and CMV disease. High-risk CMV status remains associated with CMV DNAemia, suggesting that further interventions targeting this group may be warranted.

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1102. Reconstitution of CMV-specific cell-mediated immunity during letermovir prophylaxis in hematopoietic stem cell recipients

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.1288 ◽

2020 ◽

Vol 7 (Supplement_1) ◽

pp. S581-S581

Author(s):

Maheen Abidi ◽

Jonathan Gutman ◽

Adriana Weinberg

Keyword(s):

High Risk ◽

Cell Mediated Immunity ◽

Specific Cell ◽

Cell Transplant ◽

Research Support ◽

Hematopoietic Stem ◽

Clinically Significant ◽

Cmv Disease ◽

Cmv Reactivation ◽

Research Grant

Abstract Background Patients who are cytomegalovirus (CMV) seropositive (R+) prior to hematopoietic cell transplant (HCT), have 30% incidence of clinically significant CMV reactivation in the absence of prophylaxis. At our institution, letermovir prophylaxis through Day 100 is used in CMV R+ high-risk (HR) (cord blood, haplocord, haploidentical) HCT recipients. We hypothesized that clinically nonsignificant CMV reactivation during letermovir prophylaxis may lead to reconstitution of CMV specific cell mediated immunity (CMV CMI), which may protect the host against CMV disease after letermovir discontinuation. Methods Blood samples from CMV R+ HR HCT recipients on letermovir were tested by dual color CMV specific IL2/IFNg FLUOROSpot pre-transplant and on Days 100, 182 and 360 post-transplant. Clinical and virologic information were obtained from medical records. Results Among 35 participants enrolled to date, 19 were eligible for this analysis, which included only participants with CMV CMI defined as ≥20 spot-forming cells/106 PBMC pre-transplantation and follow up ≥180 post-transplantation. Median age was 51.5 years (range 22-75), 9 were women, 9 were white non-Hispanic, 8 were Hispanic and the most common underlying malignancy was acute myeloid leukemia (n=10). 14 participants had CMV CMI reconstitution at Day 100; including 5 with and 9 without low level CMV DNAemia, defined as <5000 international units/ml in whole blood quantitative polymerase chain reaction assay, while on letermovir prophylaxis. Among the 14 participants, 11 remained free of clinically significant CMV reactivation for a median (range) of 260 (80; 260) days post-letermovir discontinuation, while 3 developed acute graft vs. host disease (aGvHD) followed by clinically significant CMV reactivation. 5 participants did not reconstitute CMV CMI at Day 100 and none of them had DNAemia while on letermovir. 1 of 5 participants without CMV CMI reconstitution or aGvHD developed CMV disease after letermovir discontinuation. Conclusion High-risk patient populations can reconstitute CMV CMI while on letermovir. Ongoing investigation will help establish predictive parameters for CMV CMI that may allow risk stratification for CMV monitoring and letermovir usage. Disclosures Maheen Abidi, MD, Merck (Research Grant or Support) Jonathan Gutman, MD, Merck (Research Grant or Support) Adriana Weinberg, MD, GSK (Grant/Research Support)merck (Grant/Research Support)

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Late Cytomegalovirus Disease after Hematopoietic Cell Transplantation (HCT) in the Preemptive Therapy Era: Characteristics, Efficacy of PCR-Based Surveillance, and Impact on Mortality

Blood ◽

10.1182/blood.v124.21.1135.1135 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1135-1135

Author(s):

Sezen Özkök ◽

Hu Xie ◽

Zach Stednick ◽

Sachiko Seo ◽

Michael Boeckh ◽

...

Keyword(s):

Viral Load ◽

High Risk ◽

Research Funding ◽

Risk Group ◽

Low Risk ◽

Preemptive Therapy ◽

Cmv Infection ◽

Cmv Disease ◽

Cmv Reactivation ◽

Overall Mortality

Abstract Background: Late cytomegalovirus (CMV) disease is a well-established complication in patients undergoing HCT and extended surveillance and preemptive therapy in high-risk patients is recommended by international guidelines. The objectives of this study were to describe the incidence, clinical characteristics and outcome of, and risk factors for the development of late CMV disease in day 100 survivors of allogeneic HCT who did and did not undergo viral load-guided preemptive therapy based on a pre-defined risk algorithm. Methods: We retrospectively analyzed medical records of 1526 HCT patients (donor or recipients seropositive), who received their first allogeneic HCT at FHCRC between 2001 and 2011 and survived to day 100. PCR-based surveillance was recommended for patients who had CMV viremia or disease before day 100 or had GVHD that required systemic treatment. Preemptive therapy was recommended for CMV DNA levels of >1000 copies per mL of plasma. We evaluated all CMV disease events occurring between day 100 and 2 years. Patients were categorized by their recommended surveillance status and, among those who were in the surveillance category, adherence to the testing schedule was examined. Cox proportional hazards models were used to evaluate the risk of late CMV disease and overall mortality. Candidate variables included risk status for PCR surveillance, CMV reactivation (before day 100 and after day 100 [as time dependent variable]), steroid use (≥ 1mg/kg/day) as well as other patient/donor and transplantation related factors; for mortality late CMV disease was also analyzed as a variable. Results: Among 1526 patients there were 118 cases of late CMV disease by 2 years (cumulative incidence 8% [95% CI- 7-9%]). The first manifestation of late CMV disease was pneumonia in 57 cases (48%), gastrointestinal disease (GI) in 54 cases (46%), and retinitis in 7 cases (6%). Fifteen percent of patients with late CMV disease (1% of cohort) had a subsequent event. Among first cases of late CMV disease 97 (82%) occurred between day 100 and 1 year and 21 (18%) occurred between 1 and 2 years after HCT. The median time to first late CMV disease was 192 days for pneumonia, 196 days for GI, and 230 days for retinitis. Extended CMV surveillance after day 100 was recommended for 1246 (82%) of patients. Late CMV disease occurred in 8.7% of patients for whom continued surveillance was recommended, compared to 2.9% of patients who were considered at low risk and were not advised to continue CMV testing. The median time to first late CMV disease event was 192 days post-transplant for the high risk group and 292 days for the low risk group. Among the 8 disease cases in patients in the low risk group, 4 cases (2 pneumonia, 2 GI) occurred in the first year and 4 (1 pneumonia, 3 GI) in the second year after HCT. In a multivariable Cox model steroid treatment after day 100 (HR=6.49; 95% CI 3.4-12.3, p<0.001), CMV reactivation after day 100 (HR=3.78; 95% CI 2.5-5.7, p<0.001), and CMV reactivation before day 100 (HR=2.07; 95% CI 1.3-3.4, p=0.003) were all strongly associated with the risk of late CMV disease. The development of CMV disease and acute GVHD (grade 3-4) before day 100 were not significantly associated with late CMV disease. Late CMV disease (HR=2.2; 95% CI 1.6-3, p<0.001) and late CMV reactivation (HR=1.63; 95% CI 1.3-2, p<0.001) were associated with increased risk of death between day 100 and 2 years after HCT. An analysis of the adherence to PCR surveillance and viral load levels among breakthrough cases will be presented at the conference. Conclusions: Late CMV disease remains an important complication after HCT. Currently recommended risk stratification parameters for extended surveillance identify most patients at risk for late CMV disease, however, occasionally late CMV disease can occur in patients that were deemed at low risk at 3 months after HCT. Also, late CMV disease can occur beyond 1 year after HCT and disease recurrence is about 15%. Overall, both late CMV infection and disease continue to be independently associated with overall mortality in the preemptive therapy era. Refined strategies are needed to further reduce the late-occurring complications of CMV infection among HCT recipients. Disclosures Boeckh: Chimerix Inc.: Consultancy, Research Funding; Viropharma Inc.: Research Funding; Genentech/Roche: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; Clinigen: Consultancy.

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Successful Use of Heterologous CMV-Reactive T Lymphocyte to Treat Severe Refractory Cytomegalovirus (CMV) Infection in a Liver Transplanted Patient: Correlation of the Host Antiviral Immune Reconstitution with CMV Viral Load and CMV miRNome

Microorganisms ◽

10.3390/microorganisms9040684 ◽

2021 ◽

Vol 9 (4) ◽

pp. 684

Author(s):

Monica Miele ◽

Alessia Gallo ◽

Mariangela Di Bella ◽

Francesca Timoneri ◽

Floriana Barbera ◽

...

Keyword(s):

T Cells ◽

Organ Transplant ◽

Solid Organ ◽

Cmv Infection ◽

Transplant Patients ◽

Cell Clones ◽

Cmv Disease ◽

Cmv Reactivation ◽

Made In

Cytomegalovirus (CMV) infection is the most significant viral infection in hosts with compromised immune systems as solid organ transplant patients. Despite significant progress being made in the prevention of CMV disease in these patients, further therapeutic strategies for CMV disease and for the CMV reactivation prevention are needed. Here, we describe the outcome of the infusion of in vitro expanded CMV-reactive T-cells, taken from a healthy CMV-seropositive donor, in a liver-transplanted recipient with a refractory recurrent CMV. In this particular case, adoptive transfer of allogenic CMV-reactive T-lymphocytes resulted in the clearance of CMV infection and resolution of the pathological manifestations of the patient. In the study we also investigated circulating miRNAs, both cellular and viral, as potential biomarkers during the course of CMV infection. The results indicate that the infusion of allogenic CMV-reactive T-cells can be an effective strategy to treat CMV infection recurrence when the generation of autologous virus specific T cell clones is not possible.

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1744. CMV Infection and Management Among Pediatric Solid-Organ Transplant Recipients

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz360.1607 ◽

2019 ◽

Vol 6 (Supplement_2) ◽

pp. S639-S639

Author(s):

Anna Sharova ◽

Despoina M Galetaki ◽

Molly Hayes ◽

Lauren Gianchetti ◽

Laura A Vella ◽

...

Keyword(s):

Organ Transplant ◽

Solid Organ Transplant ◽

First Year ◽

Invasive Infection ◽

Solid Organ ◽

Cmv Infection ◽

Research Support ◽

Free Survival ◽

Medium Risk ◽

Cmv Disease

Abstract Background Our institution provides universal CMV prophylaxis (PPX) for all high (D+/R-) and medium risk (R+) solid-organ transplant (SOT) recipients. We sought to evaluate this practice by assessing CMV infection and disease within the first year of SOT. Methods Retrospective cohort study of all children undergoing first SOT at Children’s Hospital of Philadelphia from January 2012 to October 2017. We identified recipients with CMV infection (detection of CMV DNA in body fluid/tissue with or without symptoms) and disease (symptomatic or tissue-invasive infection) in the first year after SOT. We calculated the rate of CMV infection and compared CMV-free survival based on SOT type and CMV risk using log-rank tests. Results 244 children received 246 SOTs: 90 liver, 70 kidney, 59 heart, 27 lung. In total, 39 children (16%) had 49 CMV infections in the first year after SOT, including 29% of high (n = 21/72) and 23% of medium risk recipients (n = 16/69). The fraction of each organ type with CMV infection was similar (Figure 1, P = 0.33). Among high and medium risk recipients, all of whom received PPX, the incidence rate of CMV infection in the first year post-SOT was similar: 10.1 vs. 7.8/10,000 days (P = 0.22). There were no differences in CMV-free survival by organ (Figure 2, log-rank P = 0.25) or between high and medium risk recipients (Figure 3, log-rank P = 0.46). In total, 22% (n = 10/45) of CMV infections in high/medium risk patients occurred while on PPX; half were in the setting of reduced PPX dosing or within 2 weeks of SOT. Of the 35 CMV infections post-PPX, the median time to detection of CMV after PPX was 39 days (IQR 28–98). There were 11 cases (6 high, 5 medium risk) of CMV disease: 6 CMV syndrome, 2 hepatitis, 2 pneumonitis, 1 GI disease. Valganciclovir was more often used for treatment of asymptomatic infections than for CMV disease (79% vs. 33%, P = 0.03). All-cause mortality in the first year post-SOT was similar among those with and without CMV infections (7.7 vs. 6.3%, P = 0.76) and among those with and without CMV disease (9.1 vs. 5.2%, P = 0.57). Conclusion CMV infection was common in high and medium risk SOT recipients in the first year following SOT, and most infections occurred off of PPX. Our data suggest that the highest risk period for CMV infection is in the first months after PPX, and that monitoring may be most useful after PPX has been stopped or when PPX doses are reduced. Disclosures Kevin J. Downes, MD, Merck: Grant/Research Support, Research Grant; Pfizer: Grant/Research Support.

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Pre-Transplant Ganciclovir and High-Dose Valacyclovir Prophylaxis Decrease Incidence of CMV Reactivation In High-Risk Seropositive UCBT Recipients

Blood ◽

10.1182/blood.v116.21.678.678 ◽

2010 ◽

Vol 116 (21) ◽

pp. 678-678

Author(s):

Filippo Milano ◽

Steven Pergam ◽

Hu Xie ◽

Jonathan Gutman ◽

Ivy Riffkin ◽

...

Keyword(s):

High Risk ◽

Proportional Hazards Model ◽

Conflicts Of Interest ◽

Standard Dose ◽

Cox Proportional Hazards Model ◽

Prevention Strategy ◽

High Dose ◽

Hematologic Toxicity ◽

Cmv Disease ◽

Cmv Reactivation

Abstract Abstract 678 Background: Umbilical cord blood transplant (UCBT) recipients are high risk for cytomegalovirus (CMV) complications due to delayed and insufficient immune reconstitution. Since CMV viral load has been shown to be associated with the development of disease, an intensified prevention strategy was adopted at the FHCRC (Seattle, WA) which consists of pre-transplant ganciclovir (from day -8 to day -2), and high-dose acyclovir ([HDA] 2 gm valacyclovir 3 times daily) with preemptive bi-weekly monitoring for CMV DNA in serum from day 0 until day +100. Methods: We set out to compare rates of CMV reactivation and disease through day +100 in high-risk CMV seropositive UCBT recipients who received either the intensified strategy (G+HDA) or standard dose of acyclovir/valacyclovir (SDA, acyclovir 800 mg or valacyclovir 500 mg twice daily). All patients underwent weekly plasma testing for CMV by polymerase chain reaction (PCR). Our primary outcomes of interest were any CMV reactivation or disease by day 100. Risk factors for CMV reactivation were assessed using a multivariate Cox proportional hazards model. Results: Of the 105 UCBT recipients transplanted at the FHCRC between 1/2006 and 12/2009, 61 (58%) were CMV seropositive and eligible for inclusion in the cohort. In total, 31/61 (51%) received SDA and 30 (49%) G+HDA. The median patient age was lower in the SDA group 21.3 (interquartile range [IQR] 14.8–46.7) years and 30.1 (IQR 10.1–41.8) for G+HDA group, but other demographic factors were similar. Overall, the cumulative incidence of CMV reactivation was significantly lower in the G+HDA group (60% vs. 96.7; p=0.001 [Gray's test]) (Figure 1). In patients receiving G+HDA, the median time to first positive CMV PCR occurred later (27 days [IQR 11–35]) when compared to those given SDA prophylaxis (17 days [IQR 8–25]) (p=0.26). Additionally, the G+HDA group had significantly lower initial (71 copies/mL [IQR 47–110] vs. 235 [IQR 63–760], p=0.006) and maximum PCR viral loads (VL) (170 copies/ml [IQR 88–310] vs. 3200 [1400-11000], p<0.001) when compared to those receiving SDA prophylaxis. In multivariate analyses, the G+HDA prophylactic strategy was also associated with a significant reduction in CMV reactivation (HR 0.31; 95% CI 0.16–0.58; p<0.001). Over the first 100 days following transplant, there were fewer episodes of invasive CMV disease in the G+HDA group (1/30, 3% [1 pneumonia]) than under SDA prophylaxis (5/31, 16% [1 disseminated, 2 pneumonia, and 2 GI]) (p=0.09). In the SDA group 2/5 (40%) patients died secondary to CMV disease, and an additional 2 patients developed fatal CMV pneumonia after day 100 (day 165 & 191); no CMV related death or cases of late disease developed in the group receiving G+HDA prophylaxis. There was no evidence of increased toxicity by either median and maximum creatinine levels or days to engraftment when comparing the two regimens. Conclusions: Our study demonstrates that G+HDA was effective in preventing CMV complications in UCBT recipients. This intensified prevention strategy was associated with a decreased rate of CMV reactivation and appeared to significantly alter CMV replication dynamics. Importantly, the increased valacyclovir exposure did not alter the risk for developing either renal or hematologic toxicity. Disclosures: No relevant conflicts of interest to declare.

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Intensive strategy to prevent CMV disease in seropositive umbilical cord blood transplant recipients

Blood ◽

10.1182/blood-2011-06-361618 ◽

2011 ◽

Vol 118 (20) ◽

pp. 5689-5696 ◽

Cited By ~ 69

Author(s):

Filippo Milano ◽

Steven A. Pergam ◽

Hu Xie ◽

Wendy M. Leisenring ◽

Jonathan A. Gutman ◽

...

Keyword(s):

High Risk ◽

Confidence Interval ◽

Cord Blood ◽

Umbilical Cord ◽

Umbilical Cord Blood ◽

Interquartile Range ◽

Historical Cohort ◽

Cord Blood Transplant ◽

Cmv Disease ◽

Cmv Reactivation

AbstractSeropositive umbilical cord blood transplant (UCBT) recipients are at increased risk for CMV complications. To reduce CMV complications, we adopted an intensive strategy that consisted of ganciclovir administered before transplantation (5 mg/kg intravenously daily from day −8 to day −2), high-dose acyclovir (2 g, 3 times daily) after transplanta-tion, and biweekly monitoring with a serum CMV PCR for preemptive therapy. Hazard rates and cumulative incidence of CMV complications along with days treated were compared in high-risk CMV-seropositive UCBT recipients who received the intensive strategy and a historical cohort who received a standard strategy. Of 72 seropositive patients, 29 (40%) received standard prophylaxis and 43 (60%) the new intensive approach. The hazard rate (HR) for CMV reactivation was lower for patients receiving the intensive strategy (HR 0.27, 95% confidence interval 0.15-0.48; P < .001) and led to fewer cases of CMV disease by 1 year (HR 0.11, 95% confidence interval 0.02-0.53; P = .006). In patients who reactivated, the intensive strategy also led to fewer days on CMV-specific antiviral therapy (median 42% [interquartile range 21-63] vs 70% [interquartile range 54-83], P < .001). Use of an intensive CMV prevention strategy in high-risk CMVseropositive UCBT recipients results in a significant decrease in CMV reactivation and disease.

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Poor NKG2C+ Adaptive NK Cell Recovery at Early Stage after Allo-HSCT Increased the Occurrence of Refractory Cytomegalovirus Infection

Blood ◽

10.1182/blood-2018-99-115772 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 360-360

Author(s):

Xingxing Yu ◽

Xiangyu Zhao ◽

Xunhong Cao ◽

Xuefei Liu ◽

Xuying Pei ◽

...

Keyword(s):

Nk Cells ◽

Nk Cell ◽

Solid Organ ◽

Cmv Infection ◽

Cell Recovery ◽

Post Transplantation ◽

Cell Counts ◽

Ifn Γ ◽

The Absolute ◽

Cmv Reactivation

Abstract Backgroud: Refractory cytomegalovirus (CMV) infection remains important causes of morbidity and mortality after allogeneic hematopoietic stem cells transplantation (allo-HSCT). Previous researches reported that adaptive immunity, such as CD8+ CMV-CTL, plays an important role in the in the control of refractory CMV infection. In mouse, Lanier et al. found there existed subsets of adaptive NK cells with the features of expanding, contracting after control of mouse CMV, and generating long-lived "memory" NK cells. In human, these adaptive NK cells were initially identified based on the high expression of the NKG2C which against HCMV through their cytotoxic potential and the production of TNF-α and IFN-γ upon Ab-mediated stimuli in vitro. Meanwhile, the expression levels of the NKG2C+ adaptive NK cells has been positively correlated with the NKG2C copy number. Several researchers had found that NKG2C+ adaptive NK cells persistent expanded and were potent producers of IFN-γ during CMV reactivation after solid-organ transplant or allo-HSCT. However, the role of NKG2C+ adaptive NK cells on refractory CMV reactivation were still unknown. Whether the rapid reconstitution of NKG2C+ adaptive NK cells can reduce the refractory CMV reactivation merit to be investigated. Aims:In this research, we had investigated the impacts of the quantity and quality recovery of NKG2C+ adaptive NK cells on the occurrence of refractory CMV infection. Method: At first, continuous 364 patients underwent allo-HSCT since June 2012 to February 2016 were prospectively enrolled and we retrospectively analyzed the correlationship between their donor NKG2C genotype and refractory CMV infection occurrence post transplantation. Secondly, the second cohort comprising continuous 125 patients underwent allo-HSCT since May 2016 to April 2017 were prospectively enrolled to analyzed the effect of donor NKG2C genotype on NKG2C+ adaptive NK cell recovery as well as the effect of NKG2C+ adaptive NK cell recovery on refractory CMV infection. The cytotoxicity of reconstituting NKG2C+ adaptive NK cells were evaluated against K562 cells, AD169 CMV stain infected MRC-5 cells, and UL40 peptide pulsed 721.221 cells to detect the anti-tumor or anti-CMV function of NKG2C+ adaptive NK cells. Results: Firstly, from the first cohort, we found that donor NKG2C gene deletion was an independent prognostic factor for refractory CMV reactivation (P=0.010) through the multivariate analysis. Then, through in-depth investigation from the second cohort, we found that the absolute cell counts recovery and anti-tumor function of NKG2C+ adaptive NK cells were both significantly lower in patients accepting NKG2C+/del donor than those patients accepting NKG2C+/+ donors at day 30, 90, and180, respectively after transplantation. There was no NKG2C+ adaptive NK cell recovery post transplantation in the patients who accepted NKG2Cdel/del donors. Meanwhile, anti-CMV function recovery of NKG2C+ adaptive NK cells in patients with NKG2C+/del donors were significantly lower than those patients with NKG2C+/+ donors at day 30 post transplantation. Furthermore, we further analyzed the relationship between the early reconstitution of NKG2C+ adaptive NK cells and refractory CMV infection occurrence. The patients were divided into three groups: no CMV, CMV reactivation (persistent time of CMV infection <2 weeks), and refractory CMV infection (persistent time of CMV infection>2 weeks). We found that the absolute cell counts of NKG2C+ adaptive NK cells in refractory CMV group was significantly lower than that of other two groups at day 30 transplantation. When the patients were devided into high and low level groups based on the ROC cut-off percentage of NKG2C+ adaptive NK cells (1.42%), the result revealed that the patients with lower level of NKG2C+ adaptive NK cells at day 30 post-HSCT had an higher cumulative incidence rate of refractory CMV infection (81.1%) comparing with the higher one (40.5%) (P=0.0014). Moreover, Cox regression model further demonstrated that the lower level of NKG2C+ adaptive NK cells at day 30 post-HSCT was significantly associated with refractory CMV infection (HR=2.578, 95% CI 1.379-4.21, P=0.003). Summary/Conclusion: Our results indicated that donor NKG2C deletion damaged the reconstitution of NKG2C+ adaptive NK cells after allo-HSCT, therefore increased the occurrence of refractory CMV infection post transplantation. Disclosures No relevant conflicts of interest to declare.

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Letermovir Is Effective for Prevention of Cytomegalovirus Reactivation in HLA-Haploidentical Peripheral Blood Stem Cell Transplantation with Post-Transplant Cyclophosphamide

Blood ◽

10.1182/blood-2021-152116 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2858-2858

Author(s):

Takahide Ara ◽

Yuta Hasegawa ◽

Hiroyuki Ohigashi ◽

Souichi Shiratori ◽

Atsushi Yasumoto ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Board Of Directors ◽

Cell Transplantation ◽

Cumulative Incidence ◽

Research Funding ◽

Cmv Infection ◽

Advisory Committees ◽

Cmv Disease ◽

Cmv Reactivation

Abstract [Introduction] Cytomegalovirus (CMV) infection is a common viral infection in recipients of allogeneic hematopoietic stem cell transplantation (allo-SCT). Early CMV reactivation after allo-SCT is associated with worse non-relapse mortality (NRM) and overall survival (OS). Recently, T-cell replete HLA-haploidentical SCT using post-transplant cyclophosphamide (PTCy-haplo SCT) has been developed and spread rapidly worldwide. Rationale of this strategy is assumed to be selective and cytotoxic depletion of alloreactive T cells which are responsible for graft-versus-host disease (GVHD), while preserving non-alloreactive T cells which can contribute to fight infections. However, recent studies showed that PTCy-haplo SCT was associated with the increased incidence of CMV infection. Letermovir (LET), a novel anti-CMV agent, which inhibits the CMV DNA terminase complex, was approved for the prevention of CMV reactivation in allo-SCT recipients in 2018 in some countries including Japan based on the result of a phase 3 trial. Our facility performs LET prophylaxis in allo-SCT recipient if either donor or recipient is seropositive CMV. Although LET is effective for the prevention of CMV reactivation in allo-SCT recipients, the clinical effectiveness of LET prophylaxis in PTCy-haplo SCT is not well elucidated. Based on these things, we retrospectively evaluated the efficacy of LET prophylaxis in PTCy-haplo SCT. [Methods] We retrospectively analyzed consecutive 99 recipients who received PTCy-haplo SCT at Hokkaido University Hospital from March 2013 to March 2021. We compared the cumulative incidence of CMV reactivation between the LET prophylaxis group (LET group, 33 patients) and LET non-prophylaxis group (non-LET group, 66 patients). LET was initiated on the day 0 at a dosage of 480mg daily. All patients were monitored for CMV reactivation by using the anti-CMV pp65 monoclonal antibody HRP-C7 assay at least once a week from the time of engraftment. CMV reactivation was defined as the detection of CMV antigen positive cells per 50000 white blood cells, whereas CMV disease was defined by organ dysfunction attributable to CMV. [Results] As baseline patient's characteristics were summarized in Table1, there were no difference between LET and non-LET group in terms of age, sex, underlying disease, disease risk at transplantation, prior transplantation, conditioning intensity, and CMV serostatus. All patients received peripheral blood stem cell transplantation. GVHD prophylaxis consisted of Cy (40-50 mg/kg on day 3 and 4), tacrolimus (from day 5), and mycophenolate mofetil (from day 5). The cumulative incidence of CMV reactivation at 150 days after transplantation in LET group was significantly lower than that in non-LET group (30.3% versus 69.7%; P <.001, Figure1A). Importantly, CMV disease were occurred in three patients without LET prophylaxis (gastritis, enteritis, and retinitis), but not in the patients with LET prophylaxis. The cumulative incidence of NRM at 1 year was similar between the patients with and without LET prophylaxis (17.6% versus 9.2%; P=0.366, Figure1B), as was OS at 1 year (71.5% versus 69.4%; P=0.801, Figure1C). Neutrophil engraftment was achieved in 32 patients (97%) at a median of 15 days in LET group and 64 patients (97%) at a median of 14.5 days in non-LET group (P=0.243). Furthermore, platelet engraftment was achieved in 26 patients (79%) at a median of 34 days in LET group and 57 patients (86%) at a median of 31 days in non-LET group (P=0.282). These findings suggest that LET does not affect engraftment. Interestingly, the length of hospitalization in the LET group was significantly shorter than that in non-LET group (the median, 59.5 days versus 71 days; P=0.0488), suggesting that LET suppresses CMV reactivation leading to early discharge. [Conclusion] To our best knowledge, this is the largest retrospective study about the efficacy of LET in PTCy-Haplo SCT. LET is effective for prevention of CMV reactivation in PTCy-haplo SCT. Further studies focused on the long term effect of LET prophylaxis in PTCy-haplo SCT, such as the incidence of relapse and chronic GVHD, is warranted. Figure 1 Figure 1. Disclosures Nakagawa: AbbVie GK: Research Funding; Takeda Pharmaceutical Company: Research Funding. Teshima: Gentium/Jazz Pharmaceuticals: Consultancy; Merck Sharp & Dohme: Membership on an entity's Board of Directors or advisory committees; Pfizer Inc.: Honoraria; Nippon Shinyaku Co., Ltd.: Research Funding; CHUGAI PHARMACEUTICAL CO., LTD.: Research Funding; Fuji pharma CO.,Ltd: Research Funding; Takeda Pharmaceutical Company: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis International AG: Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; TEIJIN PHARMA Limited: Research Funding; Astellas Pharma Inc.: Research Funding; Bristol Myers Squibb: Honoraria; Janssen Pharmaceutical K.K.: Other; Kyowa Kirin Co.,Ltd.: Honoraria, Research Funding; Sanofi S.A.: Research Funding.

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Use of ganciclovir for cytomegalovirus infection.

Journal of the American Society of Nephrology ◽

10.1681/asn.v212s270 ◽

1992 ◽

Vol 2 (12) ◽

pp. S270

Author(s):

T E Nevins ◽

D L Dunn

Keyword(s):

Graft Loss ◽

Solid Organ ◽

Renal Transplant Recipients ◽

University Of Minnesota ◽

Cmv Infection ◽

Seronegative Patient ◽

Patient Morbidity ◽

Infected Cells ◽

The University ◽

Cmv Disease

Ganciclovir (9-(1,3-dihydroxy-2-propoxymethyl) guanine, DHPG) is an acyclovir analog with excellent antiviral activity against human cytomegalovirus (CMV). Clinically, CMV infection occurs in from 60 to 90% of all renal transplant recipients and it is responsible for significant patient morbidity and graft loss. The likelihood of infection is closely related to the CMV status of both donor and recipient, with the greatest risk arising in the combination of a seronegative patient receiving a seropositive organ. Intracellularly, DHPG is converted to DHPG-triphosphate, which competitively inhibits DNA polymerase. This conversion is accelerated up to 10-fold in virally infected cells, providing some selectivity of action. Uncontrolled studies demonstrated DHPG efficacy in CMV disease, but experience in children remains limited. Although bone marrow suppression is a major immediate toxicity, long-term concerns about carcinogenesis and infertility mandate careful patient selection. Recently at the University of Minnesota, 93 solid organ recipients (45 renal transplants) including some children have been treated for tissue-invasive CMV with DHPG. All had a characteristic clinical picture and either a positive CMV culture or a biopsy with CMV inclusions. The patients received i.v. DHPG (10 mg/kg/day) with appropriate adjustments for renal function. In renal allograft recipients, 89% recovered within 30 days, although 21% had to be retreated with DHPG. Although no patient died, allograft survival was significantly reduced (P = 0.02). An additional subgroup of patients (N = 18) who had both biopsy-proven rejection and invasive CMV disease were simultaneously treated for both processes. All of these patients recovered from their CMV infection, but two grafts were lost to rejection.(ABSTRACT TRUNCATED AT 250 WORDS)

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