Donor Cytomegalovirus Research Articles

Predictors of CMV Reactivation and Survival in Adult Allogeneic HSCT Recipients without CMV Prophylaxis

<h3>Introduction</h3> Cytomegalovirus (CMV) is a frequent infectious complication after allogeneic HSCT, with seropositive recipients demonstrating higher mortality in registry studies. Pre-emptive treatment (PET) strategies have widely been implemented universally, however with new prophylactic agents available, at-risk groups need to be identified to ensure CMV prophylaxis is appropriately targeted. <h3>Methods</h3> Retrospective single centre cohort study of all allogeneic HSCT from 2013-2018 inclusive. Patients were assessed for clinically significant CMV infection (cs-CMVi), visceral disease and survival at a 1-year landmark analysis based on CMV serostatus and donor type (sibling [Sib]/Matched Unrelated Donor [MUD]). CMV PCR was measured by IU/mL, cs-CMVi defined as >1000iu/mL and were treated with PET ganciclovir/valganciclovir, or foscarnet if neutropenic. All MUDs received either "Rutuu" protocol high dose prednisolone (pre 2015) or Thymoglobulin ATG 4.5mg/kg (2015 onwards). <h3>Results</h3> Of 173 consecutive adult alloHSCTs, cs-CMVi developed in 54% D-/R+ vs 30% D+/R+or- (P<0.0001, Table 1 and Fig 1). This effect was more profound when assessing donor type, with cs-CMVi in 67% D-/R+ MUDs vs 38% D+/R+or- MUDs, 31% D-/R+ Sibs and 27% D+/R+or- Sibs (P<0.01, Fig 2). Overall 1-year survival of D-/R+ MUDs was significantly less than D+/R+or- MUDs (46% vs 82%, P=0.01, Fig 3). cs-CMVi was also a predictor of overall survival with a 1-year survival of 42% D-/R+ MUDs if cs-CMVi vs 64% if no cs-CMVi and, 71% D+/R+or- MUDs if cs-CMVi vs 91% if no cs-CMVi (P=0.04, Fig 4). There were 11 (6.3%) patients with evidence of CMV disease, of which 4 were D-/R+ MUDs (4/27,15%) and 4 were D+/R+ MUDs (4/48, 10%). <h3>Conclusions</h3> In alloHSCT recipients without CMV prophylaxis, CMV serostatus and donor type are significant predictors of CMV reactivation and overall survival, with CMV D-/R+ MUDs the highest risk group for cs-CMVi and mortality, therefore potential candidates for CMV prophylaxis.

CMV Viral Load Kinetics as Surrogate Endpoints for Antiviral Prophylaxis Trials

<h3>Introduction</h3> The paradigm for preventing clinically significant cytomegalovirus (CMV) infection and CMV disease after hematopoietic cell transplantation (HCT) has shifted from preemptive treatment to antiviral prophylaxis with the approval of letermovir. Previously, our group validated the use of quantitative CMV DNA viral load as a surrogate endpoint for tissue-invasive CMV disease (ASBMT 2018) in the <i>pre-emptive treatment setting</i>. <h3>Objectives</h3> To address whether CMV viral load kinetics could serve as valid surrogate endpoints for CMV disease in the <i>prophylactic setting</i>, we performed CMV viral load testing of frozen serum samples collected during a placebo-controlled randomized trial of ganciclovir (GCV) given at engraftment (Goodrich et al. Ann Intern Med 1993). Because this study pre-dated the approval of ganciclovir, CMV disease occurred in an extremely high proportion of patients, allowing us to link viral load kinetics with CMV disease, which would not be possible in the modern treatment environment. <h3>Methods</h3> We calculated each patient's CMV viral load kinetics (mean, peak, maximum change, percentage of positive viral loads) from samples collected during the first five weeks after randomization and analyzed their value as surrogates for CMV disease by 24 weeks after randomization. First, we tested each marker for fulfillment of the Prentice criteria for valid surrogate endpoints using multivariable logistic regression, including quantifying the degree to which each marker captured the effect of ganciclovir on CMV disease. Secondly, to determine the ability of the viral load markers to predict CMV disease, we developed a ‘SuperLearner' machine learning model and quantified prediction accuracy by cross-validated area under the receiver-operator characteristic curves (cv-AUCs). <h3>Results</h3> Mean, peak, change, and percentage of positive viral loads were significantly higher in the placebo group than in the ganciclovir group. See viral loads by group in Fig 1. Percentage of positive viral load satisfied Prentice criteria as a valid surrogate endpoint for CMV disease by week 24 after randomization (Fig 2). All kinetics explained greater than 80% of ganciclovir's reduction in CMV disease (mean: 86%, peak: 83%, maximum change: 95%, percent positive: 94%). We found that a SuperLearner model that included all four viral load kinetics, CMV donor serostatus, acute graft-versus-host disease, and baseline viral load predicted CMV disease with 91% cv-AUC in the placebo group, 78% in the ganciclovir group, and 82% in the combined groups (Fig 3). <h3>Conclusion</h3> We have shown for the first time in a clinical endpoint-rich, placebo-controlled antiviral prophylaxis trial that CMV viral load kinetics fulfill the Prentice criteria as valid surrogate endpoints and have high predictive value for CMV disease after HCT.

Allogeneic Hematopoietic Cell Transplantation (AHCT) in Post Infusion Cyclophosphamide (PIC) Era: The Switch from Anti-Thymocyte Globulin (ATG) to PIC for Graft Versus Host Disease (GVHD) Prophylaxis in AHCT from Alternative Donors

Aim: Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (AHCT). As GVHD prophylaxis regimen, post-transplant cyclophosphamide (Post-Cy) has been associated with less acute and chronic GVHD. Anti-Thymocyte Globulin (ATG), which is another GVHD prophylaxis regimen, could reduce the risk of chronic but not acute GVHD. Anti-thymocyte globulin (ATG) in association with a calcineurin inhibitor (CNI) and methotrexate or mycophenolate mofetil (MMF) is widely used in the setting of unrelated donor transplantation (UDT). Recent studies proned non-inferior results of haplotype matched donor transplantation (HMDT) using Post-Cy in comparison with UDT. However, there is no consensus about the optimal GVHD prophylaxis regimen or choosingwisely. Aim of this study was to compare the outcome of two GVHD prophylaxis regimens; Post-Cy used in HIDT or UDT and ATG used for unrelated donors in a single-cohort of consecutive transplant recipients. Material and Methods: Two hundred adult (17-72 years) patients who underwent HIDT and UDT with a minimum 100 days follow-up at Florence Nightingale Hospital Hematopoietic Stem Cell Transplantation Center between 2011 and 2017 were included in this study. Medical records of patients were reviewed retrospectively. Transplantation was performed in cases with high or very high DRI. HIDT was performed in 73 cases and UDT in 127 cases. One hundred eighty five out of 200 cases with a complete follow-up were included in the statistical analysis. Sixty-seven patients underwent HIDT with Post-Cy (Group 1), 97 patients with UDT receiving ATG (Group 2) and 21 with UDT receiving Post-Cy (Group 3). Patients who completed minimum 100 days post-transplantation follow-up were identified as eligible for survival analysis. Results: Median age of patients was 42.8±14.9 years. Percentage of male patients was 65.6%, 68% and 38% for HIDT with Post-Cy (Group 1), UDT with ATG (Group 2) and UDT with Post-Cy groups (Group 3), respectively, which is significantly different (p=0.03). Bone marrow was used in 58.2% patients as stem cell source in HIDT, contrary to UDT, which is below 1% (p&lt;0.0001). Median follow-up time was 398 days. Patient characteristics (Table 1), were mainly similar, such as donor age, gender, recipient cytomegalovirus (CMV) status, Karnofsky performance status, conditioning regimens, median neutrophil and platelet engraftment time, engraftment failure, acute GVHD incidence and disease status at post-transplant D100. Since the incidence of donor CMV IgG was significantly higher due to regional reasons in HIDT group, CMV activation rate was also significantly higher in this HIDT (p=0.001). No significant difference was found in Kaplan-Meier survival analysis among the HIDT with Post-Cy, UDT with ATG and UDT with Post-Cy groups, even if they were classified according to primary disease, and post transplant 100th day disease status. Transplant related mortality at 30th and 100th days were similar among three groups. Also, donor CMV status (CMV IgG positivity or negativity) and CMV reactivation was not an important factor on survival (for donor CMV status p=0.307; for CMV reactivation p=0.274). Conclusion: We did not find any significant difference among three groups with regards to survival rate and acute GVHD development. Reactivation of CMV does not effect 100th day survival. These findings support our hypothesis that post-Cy infusion regimen is an important factor for higher survival rate rather than the donor type. We believe that post Cy infusion GVHD prophylaxis platform along with MMF and CNI is maturing, proved itself as a standard immune suppressive regimen for alternative donor transplantation. The related donor switch will be expectedly soon, and we have to wait for maturation of data both on related matched and alternative donor AHCT using post Cy infusion. Disclosures No relevant conflicts of interest to declare.

91. Differential Impact of Cytomegalovirus (CMV) Donor (D) Serostatus on Rates and Kinetics of CMV Viremia among CMV Seropositive Recipients (R+) of Ex vivo T-cell Depleted (TCD) and Unmodified (CONV) Hematopoietic Cell Transplants (HCT)

BackgroundIn unmodified (CONV) HCT, CMV donor seropositivity (D+) conveys partial protection against CMV disease mediated by the transfer of donor CMV T-cell immunity through the allograft. Ex vivo T-cell depletion by CD34 selection affords a stringent depletion of donor T cells, thus transfer of donor T-cell immunity to CMV would be negligible. We evaluate the impact of CMV D serostatus on rates and kinetics of CMV viremia by Day (D)100 post-HCT in a contemporary cohort of CONV and TCD recipients from a single center.MethodsA retrospective cohort study of R+ adult recipients of first peripheral blood or marrow HCT for hematologic malignancies (excluding multiple myeloma) from June 2010 to December 2017 at MSKCC. Routine CMV monitoring by a quantitative PCR assay occurred weekly from D14 through D100. Patients were treated preemptively. CMV viral burden was assessed as the time-averaged area under the viremia curve over 100 days from HCT (AAUC) calculated as the sum of the area of trapezoids of AUC viral loads divided by the number of weeks of follow-up viremia. The median AAUC for all patients with CMV reactivation (AAUC50) was used to classify patients as CMV controllers (AAUC ≤ AAUC50) or noncontrollers (AAUC >AAUC50).ResultsOf 509 R+, 290 (57%) patients received CONV and 219 (43%) TCD HCT; from 300 (59%) D+ and 209 (41%) D− donors. In CONV, CMV viremia occurred with similar frequency in D+ (65%) and D− (62%), P = 0.6. In contrast, in TCD, CMV viremia occurred more frequently in D+ compared with D− (83% vs. 71%, P = 0.03). Among CONV, D+ was associated with lower CMV burden (median AAUC) compared with D− (0.791 vs. 1.13, respectively, P = 0.0004). In contrast, in TCD, AAUC was similar between D− and D+ (1.19 vs. 1.35; P = 0.86). Among CONV with CMV viremia, D− were more likely to be noncontrollers compared with D+ (56% vs. 31%, respectively, P = 0.001). In contrast, among TCD with CMV viremia the proportion of noncontrollers was similar between D− and D+ (61% vs. 60%, respectively; P = 1).ConclusionDonor CMV serostatus has a differential effect on rates and kinetics of CMV viremia in R+ TCD and CONV HCT recipients. D+ is associated with less CMV viremia and less CMV burden in CONV but not in TCD. Our findings, if confirmed, have implications for donor selection algorithms. Disclosures All Authors: No reported Disclosures.

Influence of donor type, stem cell source and conditioning on outcomes after haploidentical transplant for lymphoma – a LWP‐EBMT study

Haploidentical stem cell transplantation (haploSCT) is becoming a major transplant modality for lymphoma. To assess the effects of donor characteristics, stem cell source and conditioning on outcomes, we identified 474 adults with Hodgkin (HL; 240), peripheral T-cell (PTCL; 88), diffuse large B-cell (77), mantle cell (40) or follicular lymphoma (FL; 29), who received haploSCT with post-transplant cyclophosphamide. Median follow-up of alive patients was 32months. On multivariate analysis, acute graft-versus-host disease (GVHD) grade 2-4 was lower with offspring donors or bone marrow cells, whereas extensive chronic GVHD was higher in partial response at haploSCT or when using sisters, haploidentical donors beyond first degree, or female donors in male patients. Progression-free survival (PFS) was better for FL, HL and PTCL, whereas overall survival (OS) was better for HL and PTCL. Complete remission at haploSCT improved PFS and OS whereas these were negatively affected by cytomegalovirus donor positive/recipient positive status. No other donor characteristics (age, gender, human leucocyte antigen mismatch, ABO incompatibility) affected PFS or OS except use of haploidentical donors beyond first degree, which negatively affected OS. PFS and OS are mostly influenced by disease status and lymphoma subtype, supporting the use of any first degree haploidentical family member as a donor.

Low dose valganciclovir as cytomegalovirus prophylaxis in post-renal transplant recipients induced with alemtuzumab: A single-center study

ObjectivesAlemtuzumab (Ale) is a recombinant monoclonal antibody which binds to CD52 causing profound lymphodepletion, thus allowing its use in renal transplantation induction therapy. However, patients may be at increased risk for opportunistic infections, such as Cytomegalovirus (CMV). We analyzed CMV infection in renal allograft recipients administered low-dose valganciclovir (VGCV) prophylaxis with alemtuzumab induction and steroid minimization. Materials and methodsIn this retrospective analysis, 678 kidney transplant recipients were evaluated, with 606 included for analysis. Patients were excluded for receiving induction therapy other than Ale, or for lack of follow-up within 1 year. VGCV prophylaxis was stratified by recipient CMV risk status and low-dose (450 mg) VGCV was given 3 times a week to low and moderate risk patients and daily to high risk individuals. Subject records were examined for recipient demographics, donor and recipient CMV serostatus, CMV viremia, and invasive infection. ResultsOf the 606 recipients, 154 were defined as low risk for CMV infection (donor and recipient both negative, or D−/R−), 236 as moderate risk without mismatch (D+/R+), 122 as moderate risk with mismatch (D−/R+), and 94 as high risk (D+/R−). Twenty-nine (29) individuals (4.8%) tested positive by PCR for CMV viremia and 10 (1.7%) patients developed invasive CMV disease, including colitis (n = 4), esophagitis (n = 1), enteritis (n = 1), nephritis (n = 1), and pneumonia (n = 3). High risk recipients (D+/R−) accounted for the majority of invasive CMV disease (n = 5), followed by moderate risk (n = 4). CMV viremia was also more common in high risk and moderate risk (D+/R+) individuals. Overall rejection rate for our study population was 27%. ConclusionIn this institution's experience, CMV incidence was reduced compared to historically reported data by using low-dose (450 mg) VGCV prophylaxis in combination with Ale induction and steroid minimization. However, overall rejection rate was significantly higher in our population, possibly influenced by the degree of steroid minimization.

Cytomegalovirus prevention strategies and the risk of BK polyomavirus viremia and nephropathy.

Polyomavirus BK (BKV) is the cause of polyomavirus-associated nephropathy resulting in premature graft loss. There are limited data regarding the role of cytomegalovirus (CMV) infection and its prevention in developing BKV viremia and PVAN. In a prospective study, we analyzed 207 consecutive renal transplant recipients previously enrolled in 2 randomized trials evaluating different CMV prevention regimens with routine screening for BKV and CMV. Of these, 59 received valganciclovir and 100 valacyclovir prophylaxis; 48 patients were managed by preemptive therapy. At 3years, the incidence of BKV viremia and PVAN was 28% and 5%, respectively. CMV DNAemia developed in 55% and CMV disease in 6%. Both BKV viremia (42% vs 23% vs 21%, P=.006) and PVAN (12% vs 2% vs 2%, P=.011) were increased in patients treated with valganciclovir prophylaxis compared to valacyclovir and preemptive therapy. Using multivariate Cox proportional hazard regression, valganciclovir prophylaxis was independent predictor of BKV viremia (hazard ratio [HR]=2.38, P=.002) and PVAN (HR=4.73, P=.026). In contrast, the risk of subsequent BKV viremia was lower in patients with antecedent CMV DNAemia (HR=0.50, P=.018). These data suggest valganciclovir prophylaxis may be associated with increased risk of BKV viremia and PVAN. CMV DNAemia did not represent a risk for BKV.

A Longitudinal Study of γδ T Cell Subsets Post Lung Transplant: Potential Players in CMV Immunity

Purpose Cytomegalovirus (CMV) is the predominant opportunistic infection in lung transplant (LTx) recipients and there is a need to develop biomarkers that indicate CMV immunity. To this end, we have recently reported that natural killer (NK) cells expressing the activating receptor, CD94-NKG2C, may be important in the control of CMV following LTx. γδ T cells can also aid in CMV immunity, yet their role following LTx is unknown. In this study, we longitudinally assessed the phenotype of γδ T cells in the blood of LTx recipients with and without CMV reactivation. Methods Cryopreserved peripheral blood mononuclear cells (PBMC) from LTx recipients treated at the Alfred Hospital were examined by multicolour flow cytometry. Patients were stratified by risk of CMV infection into low risk (CMV donor (D) negative (-), CMV recipient (R) -, n=6), moderate risk (CMV R positive (+), n=13 (n=6 no CMV reactivation, n=7 with CMV reactivation) or high risk (CMV D+, R-) n=12 (n=5 no CMV reactivation, n=7 with CMV reactivation). CMV reactivation was classified as CMV PCR positive (>150 copies/ml) in blood and/or BAL within the first 12-months following LTx. The phenotype of γδ T cells from the LTx recipients was assessed at pre-LTx and 0.5, 1.5, 3, 6, 9, 12- and 18-months post-LTx (where available). We then compared γδ T cell phenotype between LTx recipients with and without CMV reactivation to healthy non-transplant donors (n=12). Results There was an increase in the proportion of γδ T cells expressing the Vδ1 receptor in LTx recipients compared to healthy controls, reaching significance in all CMV risk groups at 18-months post-LTx. At all time-points, there was a higher proportion of γδ T cells expressing NKG2C in moderate CMV risk recipients only without CMV reactivation compared to healthy controls. Conversely, in high CMV risk recipients with CMV, an increased proportion of γδ T cells expressed NKG2C at 18-months post-transplant compared to healthy controls. Conclusion Subsets of γδ T cells could be linked with control of CMV following LTx. Moreover, the NK cell receptor CD94-NKG2C is seemingly important in the control of CMV by multiple cell types. In conclusion, we have demonstrated that γδ T cells are an active and dynamic component of the LTx environment and may have utility as a biomarker following LTx, particularly when used in combination with NK cell analysis.

Evaluation of Cytomegalovirus-Specific T Cell Response Can Improve Risk Stratification of CMV Infection in Heart Transplant Recipients

Purpose Current assessment of risk of cytomegalovirus (CMV) infection in CMV+ heart transplant (HT) recipients is poor. This has led to universal prophylaxis, but this strategy has significant costs and side-effects. We aimed to evaluate the impact of determining CMV-specific T cell responses against 2 CMV antigens (IE-1 and pp65), using the IFN-γ ELISPOT on use of prophylaxis and the incidence of CMV infection in CMV+ HT recipients. Methods We prospectively evaluated all CMV+ HT recipients in 1 institution in whom we performed an IFN-γ ELISPOT prior to HT and 2 weeks post-HT. The ELISPOT result could be low risk (IE-1>23 spots and pp65>133 spots) or not low risk. This information plus clinical assessment led to deciding between pre-emptive therapy or prophylaxis with Valgancyclovir 900 mg daily for 3 months. We collected incidence of CMV viremia (any positive CMV PCR), CMV infection (CMV PCR>1500 IU/ml) and CMV disease and incidence of leucopenia ( Results We included 29 HT recipients with 26 IFN-γ ELISPOTs pre-HT and 28 IFN-γ ELISPOTs post-HT. Mean age was 56 years old, 24% female and 45% were emergency HT. Donor CMV serology was positive in 62% of cases. Induction therapy was given in 90% of patients. All received Tacrolimus + Mycophenolate mophetil + steroids. Figure 1 shows the main outcomes of the study. One patient died before the second IFN-γ ELISPOT determination and is not included. No patient with a low risk ELISPOT post-HT developed CMV infection, giving a positive predictive value of the test of 100%. The incidence of leucopenia was 7(39%) from 18 patients treated with prophylaxis. 2 needed G-CSF. Conclusion Evaluation of CMV-specific T cell response using the ELISPOT assay in CMV+ HT recipients can help stratify risk for CMV infection. Patients with a low risk ELISPOT 2 weeks post-HT may safely undergo pre-emptive therapy.

Mycophenolic Acid Area under the Curve Monitoring via Limited Sampling Strategy in Pediatric Heart Transplant Recipients

Purpose The study aim was to investigate exposure to mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil (MMF), after pediatric orthotopic heart transplantation (pOHT). Previous studies in pediatric kidney recipients demonstrated a relationship between MPA concentration and risk of rejection or hematologic side effects. The quantification of MPA in pOHT is not well established, and the relationship between a single-time-point-correlate and area under the curve (AUC) is lacking. We sought to assess the clinical individualization of MPA dosing after initiation of MPA AUC measurements in our patients. Methods Between April 2017 and September 2018, 81 pOHT were performed, from which 22 AUCs in 14 patients were collected via a 3 point limited sampling strategy. Indication for MPA measurement, MMF dose, frequency of dosage adjustment, and time from transplant were examined via retrospective chart review. The first year post pOHT biopsies are for concern of rejection based on frequent echocardiograms, or per DSAs, monitored at transplant and months 3, 6, and 12 thereafter. Results Median MPA AUC was 37.5 mg*h/L (range 14-216) at 61 days post-pOHT (range 11-4426). Median patient age was 10 years (range 46 days-16 years). Of 22 MPA AUCs collected, 12 warranted dosage adjustments for optimization. Within those, 9 patients' AUCs were re-measured post adjustment with 8 attaining goal range 30-60 mg*h/L. Median MMF dose was 500 mg/m^2, or 18.8 mg/kg, both twice daily. Fifty percent of all AUCs were for-cause indications: high-risk Epstein-Barr Virus donor positive, recipient negative (n=4); high-risk Cytomegalovirus donor positive, recipient negative (n=2); recent infections requiring systemic antimicrobials (n=4); and diagnosis of post transplant lymphoproliferative disorder (n=1). All but one (90.9%) of the for-cause AUC analyses merited dose adjustments. Three patients had baseline nausea; one displayed a supratherapeutic AUC. One reported nausea abatement following MMF decrease whereas two spontaneously resolved. Five reports of leukopenia were found, three with AUCs above 60 mg*h/L. All leukocyte levels normalized following MMF dosage reduction. Conclusion Patient specific tailoring of MMF via therapeutic drug monitoring of MPA AUC in pOHT may increase tolerability and diminish short and long term side effects of therapy.

Clinical practice guidelines for the provision of renal service in Hong Kong: Potential Kidney Transplant Recipient Wait-listing and Evaluation, Deceased Kidney Donor Evaluation, and Kidney Transplant Postoperative Care.

Clinical practice guidelines for the provision of renal service in Hong Kong: Potential Kidney Transplant Recipient Wait-listing and Evaluation, Deceased Kidney Donor Evaluation, and Kidney Transplant Postoperative Care.

Prophylactic Pretransplant Ganciclovir to Reduce Cytomegalovirus Infection after Hematopoietic Stem Cell Transplantation

Introduction Cytomegalovirus (CMV) reactivation remains a serious complication after allogeneic hematopoietic stem cell transplantation (HCT) occurring in 35-55% of HCT recipients. CMV reactivation can lead to adverse outcomes including end-organ damage and graft failure. Objective To reduce the incidence of CMV reactivation and disease by using prophylactic ganciclovir pretransplant. Methods We conducted a retrospective analysis of all recipient or donor CMV seropositive patients who received their first allogeneic HCT between 2012 and 2017. Ganciclovir was administered pretransplant (5 mg/kg twice daily IV from day −8 to day −2). Patients received valacyclovir or acyclovir starting day 0 until one-year posttransplant. Patients were monitored weekly with serum CMV PCR through Day 100 posttransplant. CMV reactivation was defined as a CMV viral load of more than 135 IU/ml, and was treated with preemptive therapy. All patients received GVHD prophylaxis with calcineurin inhibitor. Results Seventy-nine consecutive patients were treated. The median age was 58 years (range 20 to 72). The most common diagnoses were acute myeloid leukemia (49%) and acute lymphocytic leukemia (14%). Graft sources were matched related donor (30%), matched unrelated donor (35%), haploidentical (5%) and cord blood (29%). 43 patients (55%) received myeloablative conditioning. 36 patients (45%) received fludarabine based reduced intensity/nonmyeloablative conditioning. 24 patients (30%) had CMV reactivation with median time of reactivation of 47 days posttransplant (range 27 to 229). 22 out of the 24 (88%) patients required treatment for CMV reactivation with a median treatment duration of 37 days (range 14 to 315) and were treated with ganciclovir or foscarnet. The cumulative incidence of CMV reactivation at day 100 posttransplant was 27% with a 95% CI (18%-37%) depicted in Figure 1. There were no patients with biopsy proven CMV disease or deaths attributed to CMV reactivation or disease. The median time-to neutrophil recovery (≥500 K/ul) was 18 days and the median time to platelet recovery (≥20,000 K/ul) was 19 days. The incidence of acute GVHD Grades II-IV was 25 %. The incidence of significant kidney injury (Creatinine >2.5 mg/dL) was 2.4%. Conclusions The incidence of CMV reactivation, in this high-risk patient population, by day 100 of 27% with pretransplant ganciclovir may be improved compared to historical controls of 35-55%. The use of pretransplant ganciclovir was associated with no CMV disease and was safe, with low incidence of kidney damage. These data suggest that pretransplant ganciclovir with preemptive therapy for viral reactivation should be considered regardless of graft source. Future prospective randomized trials are needed to evaluate strategies for CMV prophylactic regimens.

A Step Forward Towards Cytomegalovirus Free Hematopoietic Stem Cell Transplantation

Introduction: Cytomegalovirus (CMV) reactivation remains one of the most serious complications after allogeneic hematopoietic stem cell transplantation (HSCT) occurring in up to 30-50% of HSCT recipients. CMV reactivation can lead to adverse outcomes including end-organ damage and graft failure. Prevention of CMV infection may improve outcomes of HSCT recipients; however, CMV reactivation can still occur in HSCT recipients despite receiving prophylactic acyclovir. In this study, we used prophylactic ganciclovir pre-transplant to reduce the incidence of CMV reactivation and CMV disease.Methods: To reduce the incidence of CMV reactivation and disease, ganciclovir was administered before transplantation (5 mg/kg twice daily intravenously from day −8 to day −2) for all donor and recipient seropositive allogeneic HSCT. This was followed by high dose valacyclovir or acyclovir starting day 0 until one year post-transplant. Patients were monitored weekly with serum CMV PCR through Day 100 post transplantation. Preemptive therapy was started for an elevated CMV viral load. CMV reactivation was defined as a CMV viral load of more than 135 IU/ml. Over the course of the analysis period, two different PCR methods were used for CMV viral load; since 2015 Roche Cobas AmpliPrep/Cobas TaqMan CMV test was implicated. CMV disease was defined as detection of CMV by one of the following diagnostic tests including: culture, immunohistochemistry staining, or histopathology examination accompanied by documentation of disease signs and symptoms of the affected organ. Statistical analysis was performed using SAS version 9.4. Logistic regression models were explored to assess the association of age, graft source, and disease type on CMV reactivation. We performed a retrospective analysis of all recipient or donor CMV seropositive patients who received their first allogeneic HSCT at the University of Virginia between 2012 and 2017.Results: Seventy-nine consecutive patients were treated. The median age was 58 years (range 20 to 72). The most common diagnoses were acute myeloid leukemia (n=39, 49%) and acute lymphocytic leukemia (n=11, 14% ). Graft sources were matched related donor, (n=24, 30%), matched unrelated donor, (n=28, 35%), haploidentical (n=4, 5%) and cord blood (n=23, 29%). 43 patients (55%) received myeloablative (CyTBI, BuCy and FluBu) conditioning. 36 patients (45%) received reduced intensity/nonmyeloablative conditioning (Flu/Cy/TBI+/- ATG, Flu/Cy/ATG ,Flu Mel, Flu Bu and Cy ATG). All patients received calcineurin inhibitor based prophylactic immunosuppressive therapy for GVHD prevention.24 patients (30%) had CMV reactivation with median time of reactivation of 47 days post-transplant (range 27 to 229). 22 out of the 24 (88%) patients required treatment for CMV reactivation with a median treatment duration of 37 days (range 14 to 315). Patients were treated with either ganciclovir or foscarnet, as clinically indicated. The cumulative incidence of CMV reactivation at day 100 post-transplant was 27% with a 95% CI (18%-37%). The median highest viral load was 2130 copies/ml (range 151 to 3,250,000 copies/ml). There were no patients with biopsy proven CMV disease. There were no deaths attributed to CMV reactivation or disease.The median time-to neutrophil recovery (ANC > 500 k/uL) was 18 days and the median time to platelet count greater than 20,000 k/ul unsupported was 19 days. The incidence of acute GVHD (Grades II-IV) was 25 %. The incidence of significant acute kidney injury defined by serum creatinine of more than 2.5 mg/dL was 2.4 %. 1 year overall survival estimate was 54% with 95% CI (42-65%). In multivariate analysis, patients who received cord blood transplants, were approximately 4 times more likely to have a CMV reactivation (Odds Ratio 3.9 with a 95% CI(1.4-10.9)), p= 0.01, than those who did not.Conclusions:The incidence of CMV reactivation by day 100 of 27% with pre-transplant ganciclovir may be improved compared to historical controls of 30-50%.The use of pre-transplant ganciclovir was associated with no CMV disease, in this single center study.The use of pre-transplant ganciclovir is safe, with low incidence of kidney damage.These data suggest that pre-transplant ganciclovir with Preemptive therapy for viral reactivation should be considered regardless of graft source. Future prospective randomized trials are needed to evaluate strategies for CMV prophylactic regimens. DisclosuresNo relevant conflicts of interest to declare.

Long-Term Impact of Cytomegalovirus Serologic Status on Lung Transplantation in the United States

Cytomegalovirus (CMV) infection has been associated with poor outcomes after solid organ transplantation. The long-term impact of donor and recipient CMV serological status on lung transplant outcomes remains unclear. Accordingly, we evaluated the impact of donor and recipient CMV status on long-term patients as well as allograft survival after single (SLT) and double lung transplantation (BLT). The Scientific Registry of Transplant Recipients was used to track all adult lung transplants in United States from May 2005 to June 2016. Patient mortality and bronchiolitis obliterans syndrome were determined up to 5 years using Cox proportional hazards modeling. Additionally, landmark analysis was performed conditional on survival at 1 year. Compared with donor negative-recipient CMV-IgG negative (D-R-), donor positive-recipient negative (D+R-) and donor positive-recipient positive (D+R+) groups had increased mortality at 1 and 5 years after BLT, with the former demonstrating highest risk. Although mortality was not increased with CMV seropositive donors after SLT at 1 year, both D+R- and D+R+ groups demonstrated greater mortality at 5 years. Risk of bronchiolitis obliterans syndrome was not affected by CMV serological status. Conditional landmark analysis confirmed that lungs from CMV seropositive donors conferred highest risk for long-term mortality. CMV seronegative recipients undergoing either BLT or SLT from CMV seropositive donors have the highest risk of long-term mortality that extends beyond the first year. Further studies are needed to determine the causes of higher mortality observed in the CMV seronegative recipients and risks and benefits of extension of CMV prophylaxis, particularly in the high-risk group.

Early conversion of pediatric kidney transplant patients to everolimus with reduced tacrolimus and steroid elimination: Results of a randomized trial.

In a 12-month, multicenter, open-label study, 106 children were randomized at 4 to 6 weeks after kidney transplantation to switch to everolimus with reduced TAC (EVR/rTAC) and steroid elimination from month 5 posttransplant or to continue standard tacrolimus with mycophenolate mofetil (sTAC/MMF) and steroids. The cumulative incidence of a co-primary efficacy end point (biopsy-proven acute rejection [BPAR], graft loss, or death from randomization to month 12) was 10.3% with EVR/rTAC and 5.8% with sTAC/MMF (difference 4.4%; P = .417). BPAR occurred in 9.6% and 5.6% of patients, respectively. Patient and renal allograft survival were 100%. The co-primary end point of mean estimated glomerular filtration rate at month 12 was 76.2 mL/min/1.73 m2 with EVR/rTAC and 72.5 mL/min/1.73 m2 for sTAC/MMF (difference 3.8 mL/min/1.73m2 ; P = .49). One EVR/rTAC patient developed posttransplant lymphoproliferative disease. Longitudinal growth and sexual maturation were equivalent between groups. The randomized drug regimen was discontinued in 34.6% and 13% of patients in the EVR/rTAC and sTAC/MMF groups, respectively (P = .024), and discontinued due to adverse events/infections in 25.0% and 11.1% of patients (P = .062). In conclusion, early conversion of pediatric kidney transplant patients from TAC, MMF, and steroids to EVR/rTAC and steroid withdrawal maintains immunosuppressive efficacy and preserves renal function.

Cytomegalovirus Infection Incidence and Risk Factors Across Diverse Hematopoietic Cell Transplantation Platforms Using a Standardized Monitoring and Treatment Approach: A Comprehensive Evaluation from a Single Institution

Human cytomegalovirus (CMV) infection and disease remains a significant cause of morbidity and mortality for hematopoietic cell transplantation (HCT) recipients. Disruption of or weak reconstitution of virus-specific cellular immune function, such as with certain HCT approaches, poses significant risk for CMV-related complications. The incidence of and risk factors for CMV infection and the nature of CMV disease were evaluated retrospectively among 356 consecutive HCT recipients transplanted at the National Institutes of Health using all graft sources, including bone marrow, peripheral blood stem cell (PBSC), and umbilical cord blood (UCB), and a range of in vivo and ex vivo approaches for graft-versus-host disease (GVHD) prophylaxis. The cumulative incidence of CMV infection was higher for CMV-seropositive recipients at 33%, regardless of donor CMV serostatus. Patients transplanted with CMV-seropositive donors had a significantly shorter duration of antiviral therapy. Among graft sources UCB was associated with the highest cumulative incidence of CMV infection at 65% and significantly longer treatment duration at a median of 36days, whereas PBSC HCT was associated with the lowest incidence at 26% and the shortest CMV treatment duration at a median of 21days. There were significant differences in the cumulative incidence of CMV infection by T cell manipulation strategy when systemic steroids were included as a risk-modifying event. Over one-third of CMV infections occurred in the setting of systemic steroid administration. CMV disease occurred in 5% of HCT recipients, with 70% of cases in the setting of treatment for GVHD. Although factors related to serostatus, graft source, and GVHD prophylaxis were associated with varied CMV infection incidence, unplanned post-HCT corticosteroid therapy contributed greatly to the incidence of both CMV infection and disease across HCT approaches, highlighting this post-HCT intervention as a key time to potentially tailor the approach to monitoring, preemptive therapy, and even prophylaxis.

Incidence of Cytomegalovirus DNAemia in Pediatric Kidney Transplant Recipients After Cessation of Antiviral Prophylaxis.

Late cytomegalovirus (CMV) infection can occur after cessation of viral prophylaxis in kidney transplant recipients, yet, timing of infection is unclear and longer duration of prophylaxis may be warranted. We conducted a retrospective cohort study of 86 children (35 CMV donor seropositive, recipient seronegative [D + R-] and 51 CMV recipient seropositive [R+]) younger than 18 years who received a kidney transplant between January 2002 and June 2014 and were treated with antiviral prophylaxis for 3 months after transplantation. Incidence of CMV DNAemia and CMV disease was determined using Kaplan-Meier analyses and risk factors were assessed using Poisson regression. Of the 86 children, 61.6% were male and median age at transplant was 13.4 years (interquartile range [IQR], 8.9-15.6) with a median follow-up of 35.2 months (IQR, 18.0-54.5). Incidence of CMV DNAemia within the first 3 months after prophylaxis cessation in CMV D + R- and CMV R+ children was 22.9% and 23.5% and incidence of CMV disease was 11.4% and 0%, respectively. Cumulative incidence of CMV DNAemia in both groups was similar (31.4%). Children who received antithymocyte globulin were more likely to develop CMV DNAemia compared with those who received anti-IL-2 (IRR, 2.98; 95% confidence interval, 1.41-6.30) after controlling for age, sex, Epstein-Barr Virus serostatus and rejection. This study demonstrates a high incidence of CMV infection after cessation of antiviral prophylaxis. These results support extension of antiviral prophylaxis beyond 3 months and/or intensive viral load monitoring to reduce risk of CMV infection in D + R- and R+ children, especially those receiving antithymocyte globulin.

Deleterious Effect of Steroids on Cytomegalovirus Infection Rate after Allogeneic Stem Cell Transplantation Depends on Pretransplant Cytomegalovirus Serostatus of Donors and Recipients

This study examined the impact of prednisone (PDN) on cytomegalovirus (CMV) infection after allogeneic stem cell transplantation (allo-SCT) according to donor and recipient CMV serostatus. Seventy-five patients underwent allo-SCT from June 2010 to July 2012. The risk of CMV infection according to donor and recipient serostatus was defined as follows: high risk (HR; D–/R+), intermediate risk (IR; D+/R+ and D+/R–), and low risk (D–/R–). Forty-five patients (60%) developed CMV infection, and 46 patients (61%) received steroids (PDN ≥ 1 mg/kg/day) to treat acute graft-versus-host disease. CMV infection was more common in those treated with steroids than in those not treated with steroids (70% versus 44%, respectively, P < .05). Overall, 40% of patients had recurrent CMV infection (50% PDN versus 24% no PDN, P < .05). Steroids had no impact on the incidence of CMV infection or its recurrence in HR patients; however, steroids did prolong the need for antiviral treatment. The incidence of CMV infection in IR patients was higher in those receiving PDN (80% PDN versus 41% no PDN, P = .01); recurrence rates were also higher (55% PDN versus 18% no PDN, P = .02). We analyzed CMV-specific immune reconstitution in the first 22 patients of the series and observed that patients on steroids had lower levels of CMV-specific lymphocytes TCD8 (P < .05 on days +60, +100, and +180) and that CMV-specific immune reconstitution (defined as lymphocytes CD8/IFN ≥ 1 cell/µL) was achieved later (after day +100 post-SCT) in the steroid group.

Cytomegalovirus infection in heart transplantation: A single center experience.

Cytomegalovirus (CMV) infection remains a major complication after heart transplantation with varying prophylaxis strategies employed. We sought to determine the impact of valganciclovir (VGC) duration on the epidemiology of CMV infections after heart transplantation. We performed a prospective cohort study of CMV donor (D) or recipient (R) seropositive heart transplant recipients from 2005 to 2012 who completed VGC prophylaxis, ranging from 3 to 12months according to serostatus and induction immunosuppression. Univariate and multivariate logistic regression was performed. Among 159 heart transplant recipients during the study period, 130 (82%) were eligible for VGC prophylaxis. CMV D/R serostatus was as follows: 24% D+/R-, 30% D+/R+, and 29% D-/R+. 65% and 21% received basiliximab and thymoglobulin induction, respectively, followed by maintenance tacrolimus, mycophenolate mofetil, and prednisone. Twenty-one (16%) recipients suffered CMV infection. There was no association with comorbidities including diabetes mellitus, chronic kidney disease, or mechanical assist devices, nor were there associations with rejection, treatments of rejection, or mortality. When VGC prophylaxis duration was stratified by ≤6 vs ≥12months, time from heart transplantation to CMV infection was delayed (median 247 vs 452days, P=.002) but there was no difference in days from VGC discontinuation to onset of CMV infection (median 72 vs 83days, P=.31). CMV infection occurred most frequently within 6-16weeks of VGC cessation, and 95% of infections occurred during the 6months post-prophylaxis period. Relative to ≤6months, ≥12months of VGC did not reduce incidence of CMV infection and only delayed time to onset. 95% of CMV infection occurs within 6months after cessation of VGC.

Cytomegalovirus Donor Seropositivity Negatively Affects Mid- and Long-term Survival After Heart Transplantation

Cytomegalovirus Donor Seropositivity Negatively Affects Mid- and Long-term Survival After Heart Transplantation