Post-transplant Cytomegalovirus Research Articles

P16.38: Healthcare Resource Utilization in Transplant Recipients With Cytomegalovirus Infection Refractory to Prior Treatment With/Without Resistance Receiving Maribavir Versus Investigatorassigned Therapy: Exploratory Analysis of the Phase 3 SOLSTICE Trial

Introduction: Increased healthcare resource utilization (HCRU) has been associated with cytomegalovirus (CMV) infection following transplantation, in particular in patients (pts) requiring >1 antiviral course. In the Phase 3 SOLSTICE study (NCT02931539), maribavir (MBV) was superior to investigator-assigned therapy (IAT; val/ganciclovir, foscarnet, cidofovir) for CMV clearance at Wk 8 and clearance plus symptom control Wk 8 maintained through Wk 16 in transplant recipients with refractory CMV infection with/without resistance (R/R). This exploratory analysis of SOLSTICE evaluated HCRU for the MBV and IAT arms. Methods: Transplant recipients with CMV R/R to prior treatment (failure to achieve >1log10 decrease in CMV DNA after ≥14 days, with/without genotyped resistance) were randomized 2:1 to MBV 400 mg BID or IAT for 8 wks with 12 wks of follow-up. After ≥3 wks of treatment, pts in the IAT arm with pre-specified criteria could enter a MBV rescue arm (8 wks’ MBV treatment, 12 wks’ follow-up). Data on hospital admissions were collected at each study visit and analyzed by treatment during the treatment and follow-up phases. Analyses included the number of pts with ≥1 hospitalization and length of hospital stay (LOS). Hospitalization rates and LOS (per person/year) were estimated using negative binomial models adjusting for exposure time. Adjusted incidence rates (IR), 95% CIs, IR ratios (IRR) and percent reduction in IRRs were calculated. Supplementary analyses described hospitalizations and LOS for the rescue arm and individual IAT groups. Results: In total, 352 pts were randomized (MBV: 235; IAT: 117), of whom 22 (18.8%) entered the MBV rescue arm. While on treatment, pts on MBV versus IAT had reductions of 34.8% in hospitalizations (p=0.021) and 53.8% in LOS (p=0.029; Table). Hospitalization rates were lower during the follow-up than treatment phase, with no differences between treatments in the follow-up (off-treatment) period (Table). The hospitalization rate in the IAT group pre-rescue with MBV (IR=6.98; 95% CI: 4.06, 12.03) was 2.54 times higher (IRR=2.54; 95% CI: 1.28, 5.04; p=0.008) than on or after rescue with MBV (IR=2.75; 95% CI: 1.81, 4.18); increased LOS pre-rescue was also noted (IRR=2.25; 95% CI: 0.72, 7.01) but not statistically significant. In the IAT arm, foscarnet pts tended to have higher hospitalizations (5.5 admissions/person/year) and longer LOS (51.7 days/person/year) during the treatment phase compared with patients on val/ganciclovir or maribavir (Figure). Conclusion: Results from this analysis quantify the HCRU experience of pts requiring treatment for post-transplant CMV. Hospitalizations and LOS were lower for pts on MBV than IAT. Pts who received MBV rescue reported lower hospitalization rates on or after rescue than pre-rescue. Reducing hospitalizations is critical for alleviating disease burden to healthcare systems. TCT2022 encore; DOI pending This study was funded by Takeda Development Center Americas, Inc. Writing and editing support was provided by Caudex (UK), funded by Takeda Development Center Americas, Inc.

New Perspectives on Antimicrobial Agents: Maribavir.

Maribavir was approved by the U.S. Food and Drug Administration in November 2021 for the treatment of adult and pediatric patients with post-transplant cytomegalovirus (CMV) infection/disease that is refractory to treatment (with or without genotypic resistance) with ganciclovir, valganciclovir, cidofovir, or foscarnet. Maribavir is an oral benzimidazole riboside with potent and selective multimodal anti-CMV activity. It utilizes a novel mechanism of action which confers activity against CMV strains that are resistant to traditional anti-CMV agents, and also offers a more favorable safety profile relative to the dose-limiting side effects of previously available therapies. Maribavir was initially studied as an agent for CMV prophylaxis in solid organ and hematopoietic stem cell recipients, but initial phase III trials failed to meet clinical efficacy endpoints. It has been more recently studied as a therapeutic agent at higher doses for refractory-resistant (R-R) CMV infections with favorable outcomes. After an overview of maribavir's chemistry and clinical pharmacology, this review will summarize clinical efficacy, safety, tolerability, and resistance data associated with maribavir therapy.

CMV Infection Following mRNA SARS-CoV-2 Vaccination in Solid Organ Transplant Recipients.

CMV Infection Following mRNA SARS-CoV-2 Vaccination in Solid Organ Transplant Recipients.

Post-Transplantation Cytomegalovirus Infection Interplays With the Development of Anastomotic Biliary Strictures After Liver Transplantation.

Background: Anastomotic biliary stricture (ABS) remains the most frequent complication after liver transplantation (LT). This study aimed to identify new anastomotic biliary stricture risk factors, with a specific focus on postoperative events. Additionally, ABS management and impact on patient and graft survival were assessed. Methods: All consecutive patients who underwent LT with duct-to-duct anastomosis between 2010 and 2019 were included. All patients who died within 90 days after LT due to non-ABS-related causes were excluded. Results: Among 240 patients, 65 (27.1%) developed ABS after a median time of 142 days (range, 13–1265). Median follow-up was 49 months (7–126). Upon multivariable analysis, donor BMI (OR=0.509, p = 0.037), post-LT CMV primoinfection (OR = 5.244, p < 0.001) or reactivation (OR = 2.421, p = 0.015) and the occurrence of post-LT anastomotic biliary fistula (OR = 2.691, p = 0.021) were associated with ABS. Anastomotic technical difficulty did not independently impact the risk of ABS (OR = 1.923, p = 0.051). First-line ABS treatment was systematically endoscopic (100%), and required a median of 2 (range, 1–11) procedures per patient. Repeat LT was not required in patients developing ABS. The occurrence of ABS was not associated with overall patient survival (p = 0.912) nor graft survival (p = 0.521). Conclusion: The risk of developing ABS after LT seems driven by the occurrence of postoperative events such as CMV infection and anastomotic fistula. In this regard, the role of CMV prophylaxis warrants further investigations.

The Clinical and Economic Benefit of CMV Matching in Kidney Transplant: A Decision Analysis.

The development of cytomegalovirus (CMV) infection after kidney transplant remains a significant cause of posttransplant morbidity, graft loss, and mortality. Despite appropriate antiviral therapy, recipients without previous CMV exposure can currently be allocated a kidney from a donor with previous CMV infection (D+R-) that carries the greatest risk of posttransplant CMV infection and associated complications. Preferential placement of CMV D- organs in negative recipients (R-) has been shown to reduce the risk of viral infection and associated complications. To assess the long-term survival and economic benefits of allocation policy reforms, a decision-analytic model was constructed to compare receipt of CMV D- with CMV D+ organ in CMV R- recipients using data from transplant registry, Medicare claims, and pharmaceutical costs. For CMV R- patients, receipt of a CMV D- organ was associated with greater average survival (14.3 versus 12.6 y), superior quality-adjusted life years (12.6 versus 9.8), and lower costs ($529 512 versus $542 963). One-way sensitivity analysis demonstrated a survival advantage for patients waiting as long as 30 mo for a CMV D- kidney. Altering national allocation policy to preferentially offer CMV D- organs to CMV R- recipients could improve survival and lower costs after transplant if appropriately implemented.

MO943: Levels of Forkhead Box P3 (FOXP3) Transcripts in Kidney Transplant Recipients is Associated With Post-Transplant Cytomegalovirus Viremia

Abstract BACKGROUND AND AIMS The forkhead box P3 (FOXP3) transcription factor is essential for the differentiation of T regulatory cells, which are major regulators of immune tolerance and immunologic activity. Quantification of the FOXP3 mRNA in peripheral blood might be clinically useful. Considering possible post-transcriptional regulation of FOXP3 mRNA, we tested the hypothesis that a low level of FOXP3 is associated with a higher risk of cytomegalovirus (CMV) viremia, in kidney transplant recipients (KTRs). METHOD Blood samples were collected the first day after transplantation from incident adult kidney transplant recipients. Ribonucleic acid was extracted from peripheral blood mononuclear cells and used in quantitative reverse transcription polymerase chain reaction. Levels of FOXP3 were measured using two primers differentiating mRNA FOXP3 and pre-mRNA FOXP3 (pre-FOXP3), both primers were normalized to the reference gene β-actin. We defined viremia with CMV as the finding of more than 1000 copies per mL of CMV DNA in plasma, at least once, within 3 months after transplantation. A ratio of FOXP3 to pre-FOXP3 was calculated and compared, using Mann–Whitney U-test according to CMV viremia status. Finally using receiver operating characteristics, we calculated are under the curve. RESULTS Of 340 patients enrolled, 24 experienced post-transplant CMV viremia. The median ratio of FOXP3 to pre-FOXP3 was lower in those diagnosed with post-transplant CMV viremia, compared to those who were not 6.8 [1.2–11.3] versus 12.2 [3.5–28.9] P &amp;lt; 0.01, respectively. Receiver operating characteristics yielded an area under the curve of 66.7% P &amp;lt; 0.01. CONCLUSION Our data shows an association between low levels of FOXP3 and risk for post-transplant CMV infection in kidney transplant recipients.

Incidence of Post-Transplant Cytomegalovirus Viremia in Patients Receiving Lungs After Ex Vivo Lung Perfusion

<h3>Purpose</h3> CMV infection following lung transplant (LTx) is associated with increased morbidity and mortality. Inflammation, infection and longer ischemic times are important risk factors for CMV infection. Ex vivo lung perfusion (EVLP) has helped to successfully increase utilization of high-risk donors over the last decade. However, the impact of EVLP on post-transplant CMV infection is unknown. <h3>Methods</h3> Single-center, retrospective analysis of all LTx recipients from 2010 to 2020. The primary endpoint was comparison of CMV viremia in recipients that received EVLP vs. non-EVLP donor lungs. CMV viremia was defined as CMV PCR > 1000 IU/mL within two years post-transplant. Secondary endpoints were time from LTx to CMV viremia, peak CMV PCR and survival. Outcomes were also compared between the different donor (D)-recipient (R) CMV serostatus matching groups. <h3>Results</h3> Included were 862 recipients of non-EVLP lungs and 389 recipients of EVLP lungs. There was no significant difference in the distribution of the CMV serostatus matching groups. 35.8% of patients in the non-EVLP group developed CMV viremia vs. 31.9% in the EVLP group (p=0.18). Median time to CMV viremia was 234 days [IQR, 179-318] in non-EVLP and 249 days [IQR, 186-313] in EVLP group (p=0.5). The mean±SD peak viremia was 4.1±0.8 log₁₀ IU/mL in the non-EVLP group and 4.2±0.8 log₁₀ IU/mL in the EVLP group (p=0.4). There was also no difference in survival of the viremic patients between the groups (log-rank p=0.8). All outcomes were similar when comparing non-EVLP and EVLP patients within each serostatus matching group (Fig.1). <h3>Conclusion</h3> Lung transplant activities have significantly increased with the use of high-risk donor lungs evaluated on EVLP. The practice of utilizing more injured donor organs via EVLP has not affected CMV viremia rates and severity in lung transplant recipients. EVLP could further provide the opportunity to pre-treat donor lungs prior to implantation, perhaps decreasing incidence of post-transplant CMV infection.

Evaluation of treatment patterns, healthcare resource utilization, and costs among patients receiving treatment for cytomegalovirus following allogeneic hematopoietic cell or solid organ transplantation

Aim Management of cytomegalovirus (CMV) infection/disease in transplant recipients may be complicated by toxicities and resistance to conventional antivirals, adding to the overall healthcare burden. We characterized treatment patterns, healthcare resource utilization (HCRU), and costs to elucidate the healthcare burden associated with CMV therapies post-transplant. Materials and methods A retrospective, longitudinal cohort study of transplant recipients using data from a US commercial insurance claims database (2013–2017) was conducted. Patients with a claim for post-transplant CMV diagnosis and anti-CMV treatment (ganciclovir, valganciclovir, foscarnet, or cidofovir) were identified (Treated CMV cohort) and compared with patients with neither a claim for CMV diagnosis nor anti-CMV treatment (No CMV cohort) for outcomes including HCRU and associated costs. Allogeneic hematopoietic cell transplantation (HCT) or solid organ transplantation (SOT) recipients were analyzed separately. Anti-CMV treatment patterns were assessed in the Treated CMV cohort. Costs were evaluated among subgroups with myelosuppression or nephrotoxicity. Results Overall, 412 allogeneic HCT and 899 SOT patients were included in the Treated CMV cohorts, of which 41.7% and 52.5%, respectively, received multiple antiviral courses. Treated CMV cohorts compared with No CMV cohorts had higher mean monthly healthcare visits per patient (allogeneic HCT: 8.83 vs 6.61, SOT: 5.61 vs 4.45) and had an incremental adjusted mean monthly cost per patient differences of $8,157 (allogeneic HCT, p < .004) and $2,182 (SOT, p < .004). Among Treated CMV cohorts, HCRU and costs increased with additional CMV antiviral treatment courses. Mean monthly costs were higher for patients with than without myelosuppression or nephrotoxicity. Limitations Results may not be generalizable to patients covered by government insurance or outside the USA. Conclusions CMV post-transplant managed with conventional treatment is associated with substantial HCRU and costs. The burden remains particularly high for patients requiring multiple treatment courses for post-transplant CMV or for transplant recipients who develop myelosuppression or nephrotoxicity.

Maribavir: First Approval.

Maribavir (LIVTENCITYTM), a cytomegalovirus (CMV) enzyme pUL97 kinase inhibitor, is being developed by Takeda Pharmaceuticals for the treatment of CMV infections. Maribavir was recently approved in the USA for the treatment of post-transplant CMV infection/disease that is refractory to treatment (with or without genotypic resistance) with ganciclovir, valganciclovir, cidofovir or foscarnet in adults and paediatric (≥ 12 years of age and weighing ≥ 35 kg) patients. This article summarizes the milestones in the development of maribavir leading to this first approval for CMV infections.

Persistence of Gastric Metaplasia of the Terminal Ileum after Post-transplant Cytomegalovirus Ileitis and Graft-versus-Host Disease

Persistence of Gastric Metaplasia of the Terminal Ileum after Post-transplant Cytomegalovirus Ileitis and Graft-versus-Host Disease

A Single Center Retrospective Analysis of Letermovir for Cytomegalovirus Prophylaxis after Allogeneic Stem Cell Transplant in Cytomegalovirus Seropositive Recipients or Donors

Background: Up to 70% of allogeneic stem cell transplant (alloSCT) recipients who are cytomegalovirus (CMV) seropositive experience CMV reactivation and up to a third are complicated by end-organ disease. Letermovir, an antiviral agent targeting CMV, is FDA-approved for prophylaxis of CMV reactivation in CMV seropositive recipients of alloSCT. 1-4 In CMV seropositive recipients, letermovir use up to week 14 after alloSCT has demonstrated a significantly lower incidence of clinically significant CMV infection (csCMVi) and an overall mortality benefit as far as 24 weeks after transplant. 5-8 However, data on csCMVi beyond 24 weeks is lacking. Additionally, more information is needed on letermovir use in patients who had prior alloSCT, are CMV seronegative, have a detectable CMV viral load but without csCMVi, and/or are high risk*.Methods: This is a single-center, retrospective, comparative cohort analysis of 524 patients who received alloSCT at Barnes-Jewish Hospital from January 2016 to June 2019. Of those, 191 patients were excluded because both the recipient and donor were seronegative for CMV. Patient information was obtained from the electronic medical record systems after IRB approval of the protocol. Gray's sub-distribution methods (while account for death as competing risk) were used to calculate the incidence of csCMVi and to assess the effect of letermovir on csCMVi. Univariate and multivariate Cox proportional hazards models were fitted for the effect of letermovir on overall survival (OS), and time-dependent Cox model was used to determine the effect of csCMVi on OS.Results: Out of 333 patients, 149 received letermovir. The median follow-up period was 13.38 months (0.033 to 63.8 months). A univariate analysis demonstrated that csCMVi was associated with worse OS (HR 2.173, 95% CI 1.602-2.948). Among those who received letermovir, there were reductions in csCMVi for the overall cohort and for high-risk patients at 100 days, 180 days, and 365 days after alloSCT. In seropositive recipients receiving seropositive alloSCT (CMV +/+), there were reductions in csCMVi at days 100, 180, and 365 after transplant. In seropositive recipients receiving seronegative alloSCT (CMV +/-), there was a reduction in csCMVi at 100 days after transplant. There was a reduction in CMV-related mortality at day 180 post-transplant (p=0.03) but not at day 365 (p=0.46). Additionally, for the overall cohort, the letermovir group showed worse OS from days 180-365 (HR 1.938, 95% CI 1.143-3.285). In CMV seronegative patients receiving seropositive SCT (CMV -/+), no difference in csCMVi was detected at days 100, 180, and 365. A landmark analysis of Day 100 IgG level effect on csCMVi incidence demonstrated that lower IgG level (<485) is associated with higher csCMVi rates after Day 100 (p=0.004). Day 100 CD4 level was not found to be predictive of csCMVi (p=0.744).Conclusion: Letermovir prophylaxis reduces csCMVi overall and in high risk and CMV seropositive patients. We observed a reduction in CMV-related mortality at 180 days after transplant with letermovir prophylaxis. A worsening of OS after day 180 and a trend towards worse non-relapse mortality was surprising and may be related to a higher degree of immunosuppression associated with post-transplant cyclophosphamide (PTCy) use, haploidentical SCT, thymoglobulin use, prior SCTs, and CMV high-risk* patients. Additionally, letermovir was stopped at day 100 at which point survival worsens and the incidence of csCMVi precipitously increases. Our results suggest that there may be additional benefit to extending letermovir therapy past day 100 in the high-risk groups, haploidentical SCT group, patients with low IgG levels at day 100, and subclinical CMV viremia.*High risk patients were defined as those receiving haploidentical, mismatched related, mismatched unrelated, umbilical cord blood, T-cell depleted graft stem cell transplants or immunosuppression with methylprednisolone > 1 mg/kg or 2 or more immunosuppressants. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Incidence of refractory cytomegalovirus infection after allogeneic hematopoietic stem cell transplantation.

Post-transplant cytomegalovirus (CMV) disease can be almost completely avoided by current infection control procedures. However, CMV reactivation occurs in more than half of patients, and some patients can develop clinically resistant CMV infections. Whether resistance is due to the host's immune status or a viral resistance mutation is challenging to confirm. Therefore, a prospective observational analysis of refractory CMV infection was conducted in 199 consecutive patients who received allogeneic hematopoietic stem cell transplantation at a single institution. Among them, 143 (72%) patients received anti-CMV drugs due to CMV reactivation, and only 17 (8.5%) exhibited refractory CMV infection. These patients had clinically refractory infection. However, viral genome analysis revealed that only one patient exhibited a mutation associated with the anti-CMV drug resistance. Clinical resistance was mainly correlated with host immune factors, and the incidence of resistance caused by gene mutations was low at the early stage after a transplantation.

Outcomes After Living Donor Liver Transplantation in Pediatric Patients with Inherited Metabolic Diseases.

BackgroundThere is no consensus about the long-term prognosis of pediatric patients with a variety of rare liver diseases but with inherited metabolic diseases (IMDs). We retrospectively reviewed the developmental outcomes of patients with IMDs undergoing living donor liver transplantation (LDLT).Material/MethodsBetween May 2001 and December 2020, of 314 pediatric patients who underwent LDLT, 44 (14%) had IMDs. The median age at LDLT was 3.0 years old (range 0–15.0 years). Associations between the post-transplant complications and graft survival rate in patients with IMDs and biliary atresia (BA) were calculated. We evaluated the safety of LDLT from heterozygous carrier donors, the prognosis of patients with IMDs who have metabolic defects expressed in other organs, and developmental outcomes of patients with IMDs.ResultsThe 10-year graft survival rates in patients with IMDs and BA were 87% and 94%, respectively (P=0.041), and the causes of graft failure included pneumocystis pneumonia, acute lung failure, hemophagocytic syndrome, hepatic vein thrombosis, portal vein thrombosis, and sepsis. The rate of post-transplant cytomegalovirus viremia in patients with IMDs was higher than that of patients with BA (P=0.039). Of 39 patients with IMDs, 15 patients (38%) had severe motor and intellectual disabilities in 4 patients, intellectual developmental disorders including epilepsy in 2, and attention-deficit hyperactivity disorder in 2. Of 28 patients with IMDs, 13 (46%) needed special education.ConclusionsThe long-term outcomes of LDLT in patients with IMDs are good. However, further long-term social and educational follow-up regarding intellectual developmental disorders is needed.

Clinical characteristics and viral load patterns in children with cytomegalovirus gastrointestinal disease after allogeneic hematopoietic stem cell transplantation.

Cytomegalovirus (CMV) reactivation in allogeneic hematopoietic stem cell transplantation (allo-HSCT) causes significant morbidity and mortality. This study aimed to investigate the clinical characteristics of children diagnosed with CMV GI disease after allo-HSCT. This was a retrospective cohort study of patients <19 years old that underwent allo-HSCT during an 11-year period. Of the 756 patients, 55.5% (n = 420) experienced post-transplant CMV DNAemia, 2.9% (n = 22) were diagnosed with proven CMV GI diseases, and the highest incidence wasfound in familial mismatched donors (5.6%, P = 0.029). CMV GI disease was diagnosed <100 days of transplant in 68.2% (n = 15/22), and 13.6% (n = 3/22) did not have concurrent CMV DNAemia. Patients were divided into five groups based on the patterns of CMV viremia initiation and duration post-HSCT. At 3 months post-transplant, lower CD4+ (P = 0.006) and CD8+ (P = 0.011) T-cell counts were observed in patients with waxing and waning CMV viral load titers >100 days post-transplant (groups 1-3) compared to those with CMV DNAemia only prior to 100 days post-transplant and those without concurrent CMV DNAemia (groups 4-5). A higher 1-year all-cause mortality was observed in groups 1-3 compared to groups 4-5 (42.8% vs. 0%; P = 0.051). Active surveillance and aggressive management of CMV reactivation is crucial, especially in children with delayed CD4+ and CD8+ T-cell reconstitution after allo-HSCT.

KIR Receptors as Key Regulators of NK Cells Activity in Health and Disease.

Natural killer (NK) cells are part of the cellular immune response. They target mainly cancer and virally infected cells. To a high extent cytotoxic activity of NK cells is regulated inter alia by signals from killer immunoglobulin-like receptors (KIR). The major histocompatibility complex (MHC) class I molecules are important ligands for KIR receptors. Binding of ligands (such as MHC I) to the KIR receptors has the important role in solid organ or hematopoietic cell transplantation. Of note, the understanding of the relationship between KIR and MHC receptors may contribute to the improvement of transplant results. Donor-recipient matching, which also includes the KIR typing, may improve monitoring, individualize the treatment and allow for predicting possible effects after transplantation, such as the graft-versus-leukemia effect (GvL) or viral re-infection. There are also less evident implications of KIR/MHC matching, such as with pregnancy and cancer. In this review, we present the most relevant literature reports on the importance of the KIR/MHC relationship on NK cell activity and hematopoietic stem cell transplantation (HSCT)/solid organ transplantation (SOT) effects, the risk of allograft rejection, protection against post-transplant cytomegalovirus (CMV) infection, pregnancy complications, cancer and adoptive therapy with NK cells.

Immunotherapy with adoptive cytomegalovirus-specific T cells transfer: Summarizing latest gene engineering techniques.

Cytomegalovirus (CMV) infection remains a major complication following allogeneic hematopoietic stem cell transplantation (HSCT). T cell response plays a critical role in inducing long‐term immunity against CMV infection/reactivation that impairs during HSCT. Adoptive T cell therapy (ACT) via transferring CMV‐specific T cells from a seropositive donor to the recipient can accelerate virus‐specific immune reconstitution. ACT, as an alternative approach, can restore protective antiviral T cell immunity in patients. Different manufacturing protocols have been introduced to isolate and expand specific T cells for the ACT clinical setting. Nevertheless, HLA restriction, long‐term manufacturing process, risk of alloreactivity, and CMV seropositive donor availability have limited ACT broad applicability. Genetic engineering has developed new strategies to produce TCR‐modified T cells for diagnosis, prevention, and treatment of infectious disease. In this review, we presented current strategies required for ACT in posttransplant CMV infection. We also introduced novel gene‐modified T cell discoveries in the context of ACT for CMV infection. It seems that these innovations are enabling to improvement and development of ACT utilization to combat posttransplant CMV infection.

Abstract 436: Whole body imaging of genetically labeled hematopoietic stem cells in human subjects

Abstract Background: Despite decades of experience with bone marrow transplantation, there has not been prior whole body visualization of the engraftment of hematopoietic stem cell (HSC) in bone marrow in humans. The herpes simplex virus type 1 sr39 thymidine kinase (sr39tk) gene is a positron emission tomography (PET) reporter/suicide gene that can be used to genetically label cells and track them in vivo based on the ability to retain the PET tracer [18F]FHBG, which is a penciclovir analogue. Methods: Three patients with metastatic sarcoma were treated with gene-modified autologous CD34+ peripheral blood stem cells (PBSCs) transduced with a lentiviral vector encoding both a transgenic T-cell receptor against the tumor antigen NY-ESO-1 and the sr39tk reporter/suicide gene after a reduced intensity conditioning regimen of busulfan and fludarabine. These gene-modified stem cells were co-administered with gene-modified autologous T-cells also encoding the NY-ESO-1 T-cell receptor. The primary endpoint was safety and feasibility, while an exploratory endpoint was standardized uptake value of [18F]FHBG PET between post-transplant day +25 and day +120 scans to study the biodistribution of the gene-modified PBSCs and progeny T cells. Results: Two patients (NYSCT-01 and NYSCT-03) demonstrated robust engraftment the gene-modified PBSCs in bone marrow niches by day +25-30, as demonstrated by whole body [18F]FHBG PET. PET signal was evident throughout the body in the bone marrow in the scalp, jaw, vertebrae, ribs, pelvis, femur and other bones with significant areas of bone marrow. The third patient (NYSCT-05), whose product had much lower transduction efficiency, did not display any engraftment signal at day +28. Patient NYSCT-01 demonstrated loss of [18F]FHBG signal at day +120, with no detectable T-cell progeny in peripheral circulation. Patient NYSCT-03 developed a post-transplant de novo multidrug-resistant cytomegalovirus (CMV) viremia at day +58 which ultimately required treatment with systemic ganciclovir, and passed away prior to her day +120 PET scan. Patient NYSCT-05 developed a post-transplant CMV reactivation viremia on day +45, which responded to oral valganciclovir treatment. Conclusions: PET imaging allowed visualization of the successful engraftment of sr39tk reporter gene-labeled HSCs in bone marrow niches. Further studies are needed to determine mechanisms of loss of engraftment due to immunogenicity of the sr39tk gene, or insufficient transduction efficiency. Citation Format: Theodore S. Nowicki, Beata Berent-Maoz, Cristina Puig-Saus, Paula Kaplan-Lefko, Ignacio Baselga Carretero, Ameya Champhekar, Giuseppe Carlucci, Mignonette Macabali, Ivan Perez Garcilazo, Agustin Vega-Crespo, Jonathan Rodriguez, Bartosz Chmielowski, Arun Singh, Martin Allen-Auerbach, Shaojun Zhu, Roger Slavik, Begonya Comin-Anduix, John Williams, Antoni Ribas. Whole body imaging of genetically labeled hematopoietic stem cells in human subjects [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 436.

Efficacy and Safety According to the Dose of Valganciclovir for Cytomegalovirus Prophylaxis in Transplantation: Network Meta-analysis Using Recent Data

Valganciclovir is used to prevent posttransplant cytomegalovirus (CMV) infection among patients undergoing kidney transplant. However, the optimal dose remains controversial because continuous use decreases kidney function and can induce leukopenia. The purpose of this study was to identify the appropriate dose of valganciclovir for preventing CMV using network meta-analysis. We searched the Cochrane Central Register, Ovid MEDLINE, EMBASE, Cumulative Index to Nursing and Allied Health, and Web of Science databases for studies published through April 15, 2017, evaluating 900-mg and 450-mg valganciclovir. We performed direct and indirect network meta-analysis usingBayesian models and generated rankings of different doses of valganciclovir by generating a mixed-treatment comparison. Twenty-three studies involving 3478 participants were included. Compared with the control group, there was no difference in the incidence of CMV infection between the low-dose (450 mg) (odds ratio [OR], 0.79; 95% confidence interval [CI], 0.50-1.40) and high-dose (900 mg) (OR, 1.0; 95% CI, 0.61-1.60) groups. Low-dose valganciclovir had the best probability (71.1%) for decreasing CMV infection. Leukopenia was significantly more common in the high-dose group than in the control group (OR, 4.3; 95% CI, 2.69-7.10) and in the low-dose group (OR, 2.9; 95% CI, 1.88-4.67), but there was no significant difference in the incidence of leukopenia between the low-dose and control groups (OR, 1.5; 95% CI, 0.99-2.20). The incidence of CMV was not different based on the dose of valganciclovir, although the tendency for CMV infection was decreased at 450 mg. However, the low dose of valganciclovir significantly reduced the incidence of leukopenia.

Association between Antiviral Prophylaxis and Cytomegalovirus and Epstein-Barr Virus DNAemia in Pediatric Recipients of Allogeneic Hematopoietic Stem Cell Transplant.

Background: Epstein–Barr virus (EBV) and cytomegalovirus (CMV) infections can have serious consequences during the period of aplasia and lymphopenia following hematopoietic stem cell transplantation (HSCT). Large pediatric cohort studies examining the effect of antiviral prophylaxis against these viruses are scarce. The present study aimed to analyse the potential effect of antiviral prophylaxis (acyclovir and famciclovir) on active post-transplant EBV and CMV infection in a pediatric cohort of allogeneic HSCT recipients. Methods: We used data from the TREASuRE cohort, consisting of 156 patients who had a first allogeneic HSCT, enrolled in four pediatric centers in Canada between July 2013 and March 2017. Follow-up was performed from the time of transplant up to 100 days post-transplant. Adjusted hazard ratio (HR) with 95% confidence intervals (CI) for the association between antiviral prophylaxis with acyclovir and/or famciclovir and EBV and CMV DNAemia was estimated using multivariate Cox regression models. Results: The post-transplant cumulative incidence of EBV and CMV DNAemia at 100 days of follow-up were, respectively, 34.5% (95% CI: 27.6–42.6) and 19.9% (95% CI: 14.5–27.1). For acyclovir, the adjusted hazard ratio (HR) for CMV and EBV DNAemia was 0.55 (95% CI: 0.24–1.26) and 1.41 (95% CI: 0.63–3.14), respectively. For famciclovir, the adjusted HR were 0.82 (95% CI: 0.30–2.29) and 0.79 (95% CI: 0.36–1.72) for CMV and EBV DNAemia, respectively. Conclusion: The antivirals famciclovir and acyclovir did not reduce the risk of post-transplant CMV and EBV DNAemia among HSCT recipients in our pediatric population.

Cytomegalovirus Infection and the Implications of Drug-Resistant Mutations in Pediatric Allogeneic Hematopoietic Stem Cell Transplant Recipients: A Retrospective Study from a Tertiary Hospital in China

IntroductionDrug-resistant cytomegalovirus (CMV) infection remains a challenge in the management of pediatric recipients of hematopoietic stem cell transplantation (HSCT). In this study, we retrospectively reviewed the clinical data on pediatric recipients of HSCT and identified known and unknown drug-resistant CMV variants.MethodsA total of 221 children underwent allogeneic HSCT between October 2017 and November 2019 at Shenzhen Children’s Hospital; of these, 35 patients were suspected of having drug-resistant CMV infections and were tested for drug-resistant mutations in the UL97 and UL54 genes by Sanger sequencing.ResultsMutations in UL97 or UL54, or in both, were detected in 11 patients. Most of these mutations have not been previously reported. The UL97 mutation (A582V) was detected in only one patient who also harbored two UL54 mutations (T760X and R876W). One patient with both the G604S and T691A mutations in the UL54 gene died of CMV pneumonia. We investigated the risk factors associated with the development of drug-resistant CMV infection. Patients in whom both the donor and recipient had positive CMV serostatuses were less likely to have drug-resistant mutations (Fisher’s exact test, p < 0.05).ConclusionNewly and previously detected CMV mutations in UL97 and UL54 may be associated with the development of drug-resistant CMV infection. The detection of these mutations may provide guidance for the management of post-transplant CMV infections.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40121-021-00452-4.