Hematopoietic Transplant Recipients Research Articles

How we treat diarrhea in pediatric transplant patients: a brief review.

Diarrhea is a common problem faced by both hematopoietic and solid organ transplant recipients. The differential diagnosis is wide, ranging from infectious to non-infectious causes and from benign to emergent illness. Here we present two patients with diarrhea and discuss our approaches to the diagnostic evaluation and management of transplant recipients with diarrhea. We also include a review of the literature and discuss areas in need of further study.

Immune Profiling of Respiratory Syncytial Virus (RSV) for the Development of Targeted Immunotherapy

Introduction: RSV-associated respiratory viral infections are a major public health problem affecting the immunologically naïve/compromised population. For example, RSV-induced bronchiolitis and pneumonia are the leading cause of hospitalization in infants and young children worldwide, while in adult allogeneic hematopoietic transplant (HCT) recipients the incidence of progression from upper to lower respiratory tract infection (LRTI) is 40-60%, with mortality rates as high as 80%. At the national level, the Fall 2022-Spring 2023 RSV surge translated into a sharp rise in hospitalization rates surpassing last season's respective rate by almost 5-fold (https://www.cdc.gov/rsv/research/rsv-net). Our group has previously demonstrated the feasibility, safety and clinical efficacy of administering allogeneic ex vivo expanded multivirus-specific T cells (multi-VSTs) as a banked, off-the-shelf product for the treatment of EBV, CMV, BKV, HHV6, AdV and SARS-CoV-2 infections/disease in immunocompromised individuals. Given the RSV-associated morbidity and the paucity of therapeutic agents, we sought to characterize the cellular immune responses to RSV with a view to developing a targeted T-cell therapy product for those at highest risk of severe disease (i.e. HCT recipients, elderly/immunocompromised patients). Methods: To first identify immunogenic and protective RSV antigens we exposed PBMCs from healthy adult donors to pepmixes (overlapping peptide libraries) spanning the 11 RSV-encoded antigens and found that 7 induced highly reactive T cells. However, Nucleoprotein (N) and Fusion Protein (F) proved to be immunogenic in all donors and were thus advanced for VST manufacturing. We subsequently utilized our optimized VST manufacturing process and culture in a G-Rex device in medium supplemented with activating cytokines to generate RSV-specific VSTs (RSV-STs) with activity against this combination of immunodominant targets. Results: We achieved a mean 5.2±1-fold expansion (mean±SEM; n=13) of cells that were comprised almost exclusively of CD3+ T cells (94.08±1.15%), with a mixture of cytotoxic (CD8+; 28.91±5.16%) and helper (CD4+; 71.09±5.15%) T cells. These cells had a phenotype consistent with effector function and memory potential, as evidenced by upregulation of the activation markers CD25, CD69, and CD28 and expression of central (CD45RO+/CD62L+) and effector memory markers (CD45RO+/CD62L-) with minimal expression of exhaustion-related markers such as PD1, Tim3 and LAG3. The anti-viral activity of the expanded cells was confirmed in an IFNγ ELISpot using both stimulating antigens as an immunogen and all lines proved to be reactive against the target antigens (N: 3587±939 SFC/2x10 5; F: 3526±743). As demonstrated by surface and intracellular flow cytometry, the immune response was mediated by both CD4+ and CD8+ T cell subsets through IFNγ/TNFα production and upregulation of activation/costimulatory markers. Reactive cells were polyfunctional and primarily Th1-polarized as evidenced by IFNγ, Granzyme-B, IL-2 and GM-CSF production measured by FluoroSpot and Luminex array. Finally, the expanded cells were able to kill viral pepmix-loaded autologous PHA blasts with minimal/no activity against non-antigen-expressing autologous and allogeneic targets. Conclusion: Healthy donor-derived RSV-STs are Th1-polarized, polyfunctional and selectively able to kill viral antigen-expressing targets with no auto- or alloreactivity, indicative of their safety for clinical use. A clinical trial evaluating their safety and activity in HCT recipients as part of an off-the-shelf multi-respiratory virus-directed product is currently underway (NCT04933968, https://clinicaltrials.gov).

Adenovirus Infection in Hematopoietic and Solid Organ Paediatric Transplant Recipients: Treatment, Outcomes, and Use of Cidofovir.

human adenovirus (hAdV) infection constitutes an important cause of morbidity and mortality in transplant recipients, due to their immune status. Among drugs currently available, cidofovir (CDF) is the most prescribed. Retrospective study of hAdV infection in paediatric transplant recipients from a tertiary paediatric centre, describing characteristics, management, and outcomes, and focused on the role of CDF. 49 episodes of infection by hAdV were detected during a four-year period: 38 episodes in patients that received allogeneic hematopoietic stem cell transplantation (77.6%) and 11 in solid organ transplant recipients (22.4%). Twenty-five patients (52.1%) were symptomatic, presenting mainly fever and/or diarrhoea. CDF was prescribed in 24 patients (49%), with modest results. CDF use was associated with the presence of symptoms resulting in lower lymphocyte count, paediatric intensive care unit admission, and high viral load. Other therapeutic measures included administration of intravenous immunoglobulin, reducing immunosuppression, and T-lymphocyte infusion. Despite treatment, 22.9% of patients did not resolve the infection and there were three deaths related to hAdV infection. All-cause mortality was 16.7% (8 episodes) by 30 days, and 32.7% (16 episodes) by 90 days, of which, 3 episodes (3/16, 18.8%) were attributed to hAdV directly. hAdV infection had high morbidity and mortality in our series. CDF use is controversial, and available therapeutic options are limited. Transplant patients with low lymphocyte count are at higher risk of persistent positive viremias, and short-term survival of these patients was influenced by the resolution of hAdV infection.

Neutropenia Secondary to SARS-Cov2 Vaccination in Post-Hematopoietic Stem Cell Transplant (HSCT) Patients.

SARS-Cov2 s, caused a high mortality in patients with some degree of immunosuppression, like those that receive a hematopoietic progenitor transplant. Since December 2020, several vaccines have been developed having been key in decreasing complications and mortality in this group of patients. Different articles have described the presence of thrombopenia related to the administration of vaccines, however, there are few data on the occurrence of neutropenia as a side effect after administration. We present several cases of neutropenia (defined as absolute neutrophil count (ANC) less than 2,000/mm3), after vaccination in hematopoietic progenitor transplant (HPT) recipients performed in our center during 2021.
  

Features of cytomegalovirus DNAemia and virus-specific T-cell responses in allogeneic hematopoietic stem-cell transplant recipients during prophylaxis with letermovir.

There is scarce information on the natural kinetics of cytomegalovirus (CMV) DNAemia and dynamics of CMV-specific T-cell reconstitution in allogeneic hematopoietic transplant recipients (allo-HSCT) undergoing letermovir (LMV) prophylaxis. Twelve adult CMV-seropositive high-risk recipients (median age, 53 years; 9 males/3 females) undergoing LMV prophylaxis and 13 non-LMV allo-HSCT controls (median age, 58 years; 7 males/6 females) were included. CMV DNAemia in plasma was monitored by real-time polymerase chain reaction. Preemptive antiviral therapy (PET) was administered upon detection of ≥1500IU/ml. CMV-specific interferon-gamma (IFN-γ)-producing CD8+ and CD4+ T cells were enumerated by flow cytometry around days +30, +60, and +90 after allo-HSCT. Ex vivo experiments assessing of the potential effect of LMV on CMV-specific T-cell expansion in a single CMV-seropositive donor were also conducted. Five LMV patients (41.6%) developed CMV DNAemia that cleared spontaneously. Four patients (33.3%) developed CMV DNAemia after LMV cessation, of which two required PET. Nine non-LMV patients (69.2%) developed CMV DNAemia (five required PET). The percentage of LMV and non-LMV patients exhibiting detectable CMV-specific T-cell responses was comparable (7/10 vs. 10/13; p=.71). Nevertheless, median CMV-specific CD4+ and CD8+ T-cell counts were lower in LMV patients by days +60 (p=.006 and .02, respectively) and +90 (p=.08 and .02). Ex vivo, CMV-specific CD8+ T cells expanded to the same level either in the presence (19.8%) or in the absence of LMV (20.6%). In our series, episodes of CMV DNAemia in LMV patients cleared spontaneously. A diminished degree of CMV-specific T-cell reconstitution in LMV patients compared to non-LMV patients was observed.

2119. Predictive Value of the Immunodeficiency Scoring Index for COVID-19 Related Outcomes in Hematopoietic Transplant Recipients

Abstract Background The Coronavirus Disease 2019 (COVID-19) has significantly impacted cancer patients with some reported mortality as high as 25%. The Immunodeficiency Scoring Index (ISI) was developed as a prognostic tool in allogeneic hematopoietic cell transplant (allo-HCT) recipients with respiratory syncytial virus but also for other respiratory viruses to predict severe infections and mortality. The purpose of our study was to correlate the ISI in HCT recipients with COVID-19 and associated complications such as hospitalization, supplemental oxygen use, and mortality. Methods We performed a cohort study of HCT recipients of all ages with COVID-19 between March 2020 and October 2021. We included only patients who were diagnosed by a PCR-based assay. We excluded patients for whom an ISI score, as previously described, could not be calculated. Outcomes of interest included 60-day mortality, hospital and ICU admission due to COVID-19, and supplemental oxygen requirements. A univariate analysis using Fischer exact testing for nominal variables was performed. Results Out of the 219 HCT with COVID-19, 101 were excluded due to alternative methods of diagnosis (13), lack of laboratory values needed to calculate an ISI at time of COVID-19 diagnosis (79), or COVID-19 diagnosed prior to transplant (9). Out of the remaining 118 patients, the median age was 60 years (range 6-85), most were male (56%), Caucasian (57%), and had no smoking history (64%). Most patients had an alloHCT (66%) with matched related donor [MRD] (25%), or matched unrelated donor [MUD] (21%) (Table 1). Median time from transplant to COVID-19 was 615 days (range 2-5692), median ISI was 3 (range 0-11), and 92% of patients were unvaccinated prior to COVID-19 (Table 1). On univariate analysis, an ISI of moderate to high (score ≥3) was associated with COVID-19 related hospitalization [p=0.0147] and an ISI ≥ 4 was associated with 60-day all-cause (p=0.045) and COVID-19-related (p-0.019) mortality (Table 2). Table 1: Patient Characteristics Abbreviations: Hematopoietic Cell Transplant (HCT); Chronic Obstructive Pulmonary Disease (COPD); Chronic Kidney Disease (CKD); End-Stage Renal Disease (ESRD); Acute Lymphocytic Leukemia (ALL); Acute Myeloid Leukemia (AML); Myelodysplastic Syndrome (MDS); Chronic Lymphocytic Leukemia (CLL); Chronic Myelogenous Leukemia (CML) Myeloproliferative Disorder (MDS); Matched Related Donor (MRD); Matched Unrelated Donor (MUD); Mismatched Unrelated Donor (MMUD); Graft versus Host Disease (GvHD); Lower Respiratory Tract Infection (LRI); White Blood Cell (WBC); Absolute Neutrophil Count (ANC); Absolute Lymphocyte Count (ALC). Table 2: Univariate Analysis of Outcomes due to COVID-19 in HCT Recipients Abbreviations: Immunodeficiency Scoring Index (ISI); Hematopoietic Cell Transplant (HCT); Allogenic (Allo); Autologous (Auto); Lower Respiratory Infection (LRI); High-Flow Nasal Cannula (HFNC) Figure 1: Survival Curve (Kaplan-Meier Curve) Comparing Time to Death in Patients with an ISI Score of 4 or Greater. (Log-rank 0.0295) Conclusion An ISI of 4 or greater was a prognostic marker for worse outcomes such as COVID-related and all-cause mortality in HCT recipients. Whether an aggressive and prompt management of high-risk patients with COVID-19 may impact these outcomes needs to be determined in future studies. Disclosures Gabriella Rondon, MD, Omeros: Advisor/Consultant Ella Ariza-Heredia, MD, MERCK: Grant/Research Support Elizabeth Shpall, MD, Adaptimmune: Advisor/Consultant|Affimed: License agreement|Axio: Advisor/Consultant|Bayer Helathcare Pharmaceuticals: Honoraria|Fibroblasts and FibrioBiologics: Advisor/Consultant|Navan: Advisor/Consultant|NY Blood Center: Advisor/Consultant|Takeda: License agreement Roy F. Chemaly, MD/MPH, Karius: Advisor/Consultant|Karius: Grant/Research Support.

Recent Advances in Adult Post-Transplant Lymphoproliferative Disorder.

PTLD is a rare but severe complication of hematopoietic or solid organ transplant recipients, with variable incidence and timing of occurrence depending on different patient-, therapy-, and transplant-related factors. The pathogenesis of PTLD is complex, with most cases of early PLTD having a strong association with Epstein-Barr virus (EBV) infection and the iatrogenic, immunosuppression-related decrease in T-cell immune surveillance. Without appropriate T-cell response, EBV-infected B cells persist and proliferate, resulting in malignant transformation. Classification is based on the histologic subtype and ranges from nondestructive hyperplasias to monoclonal aggressive lymphomas, with the most common subtype being diffuse large B-cell lymphoma-like PTLD. Management focuses on prevention of PTLD development, as well as therapy for active disease. Treatment is largely based on the histologic subtype. However, given lack of clinical trials providing evidence-based data on PLTD therapy-related outcomes, there are no specific management guidelines. In this review, we discuss the pathogenesis, histologic classification, and risk factors of PTLD. We further focus on common preventive and frontline treatment modalities, as well as describe the application of novel therapies for PLTD and elaborate on potential challenges in therapy.

595. Letermovir (LTV) for Secondary Cytomegalovirus (CMV) Prevention in High Risk Hematopoietic Cell Transplant (HCT) Recipients: Interim Results of a Single Center, Open Label Study

BackgroundLetermovir (LTV) is effective for prevention (ppx) of primary clinically significant CMV infection (csCMVi) in the first 100 days after hematopoietic cell transplant (HCT). Data on LTV for secondary ppx is limited. We report on the efficacy and safety of LTV administered for 14 weeks as secondary CMV ppx.MethodsPatients (pts) enrolled in an open label study of LTV (ClinicalTrials.gov identifier: NCT04017962) from August 2019 through February 2021 were analyzed. Key eligibility criteria were: CMV high risk (receipt of mismatched and/or T-cell depleted HCT and/or graft versus host disease (GVHD) requiring systemic immunosuppressants) AND prior csCMVi with either undetectable CMV (≤ 136 IU/mL) or ≥ 2 consecutive values < 300 IU/mL at enrollment. Pts with breakthrough csCMVi on LTV or history of LTV resistance were excluded. LTV was administered for 14 weeks or csCMVi whichever occurred first. The study duration was 24 weeks. CMV was monitored per standards of care. The primary endpoint was csCMVi by week 14. Secondary endpoints were csCMVi by week 24, LTV resistance, CMV end-organ disease (EOD) and adverse events (AE) at least possibly related to LTV. ResultsOf 20 pts analyzed, the median age was 58 years (interquartile range [IQR] 46-63); 17 (85%) pts were CMV seropositive, 7 (35%) received mismatched HCT (haploidentical 3, cord blood 3; mismatched unrelated 1), 9 (45%) received CD34 selected allograft and 9 (45%) had GVHD at enrollment. Fourteen (70%) pts had received prior LTV. The median time from HCT to enrollment was 156 (IQR 37-244) and 55 (IQR 40-69) days for pts with and without prior LTV, respectively (P=0.16). CMV at enrollment was < 136IU/mL for 8 (40%) pts. By week 14, 4 (20%) pts developed csCMVi at median 48 days (range 40-66). Resistance testing performed in 3 of the 4 pts, identified LTV resistance mutations in 2 pts. There were no AEs related to LTV, and none developed EOD. Two pts developed csCMVi in the follow up phase. Three pts died during follow up (due to relapse, treatment related toxicity and GVHD), and four pts are in follow up.ConclusionLTV secondary prophylaxis was safe and prevented recurrent csCMVi in 80% of high risk patients, including patients with prior LTV exposure. Our data supports the utility of LTV for secondary CMV prevention following HCT.Disclosures Boglarka Gyurkocza, MD, Actinium Pharma, Inc. (Grant/Research Support, Research Grant or Support) Genovefa Papanicolaou, MD, ADMA biologics and Siemens Healthineers (Consultant, Other Financial or Material Support)AlloVir (Consultant, Other Financial or Material Support)Amplyx (Scientific Research Study Investigator, Other Financial or Material Support)Astellas (Consultant, Grant/Research Support, Scientific Research Study Investigator, Research Grant or Support, Other Financial or Material Support)Behring (Consultant, Other Financial or Material Support)Chimerix (Consultant, Grant/Research Support, Scientific Research Study Investigator, Research Grant or Support, Other Financial or Material Support)Cidara (Consultant, Other Financial or Material Support)Merck & Co (Consultant, Grant/Research Support, Scientific Research Study Investigator, Research Grant or Support, Other Financial or Material Support)Partners Therapeutics (Consultant, Other Financial or Material Support)Shionogi (Consultant, Other Financial or Material Support)Shire/Takeda (Consultant, Grant/Research Support, Scientific Research Study Investigator, Research Grant or Support, Other Financial or Material Support) Genovefa Papanicolaou, MD, allovir (Individual(s) Involved: Self): Consultant; amplyx (Individual(s) Involved: Self): Consultant; behring (Individual(s) Involved: Self): Consultant; Merck&Co (Individual(s) Involved: Self): Consultant, Investigator and received funding and consulting fees from Merck, Chimerix, Shire and Astellas, Research Grant or Support; octapharma (Individual(s) Involved: Self): Consultant; Partners Therapeutics (Individual(s) Involved: Self): Consultant; takeda (Individual(s) Involved: Self): Consultant, Scientific Research Study Investigator

20. Cost-Effectiveness of Recombinant Zoster Vaccine for Vaccinating Immunocompromised Adults Against Herpes Zoster in the United States

BackgroundIndividuals who are immunocompromised (IC) due to disease or therapy are at increased risk of herpes zoster (HZ), with HZ cases in IC populations also resulting in increased health care resource use and costs as compared with the immunocompetent population. This study assesses the cost-effectiveness of recombinant zoster vaccine (RZV) versus no vaccine for the prevention of HZ in IC adults aged ≥ 18 years in the United States (US).MethodsA Markov model with a one-year cycle length was developed to follow a hypothetical cohort of one million IC individuals for a 30-year time horizon. The model estimates health and cost outcomes associated with RZV versus no vaccine. The base-case analysis considered hematopoietic stem cell transplant (HSCT) recipients who were assumed to remain IC for five years post-transplant. Second-dose compliance was assumed to be 100%, with efficacy and waning inputs based on clinical trial data. Epidemiological, cost, and utility inputs were obtained from standard US sources and published literature. Costs and quality-adjusted life-years (QALYs) were discounted at 3% per year. Sensitivity, threshold, and scenario analyses were conducted, including scenarios of four other IC conditions.ResultsIn the modeled hypothetical cohort of one million HSCT recipients, RZV resulted in 116,790 fewer HZ cases and 21,446 fewer postherpetic neuralgia cases versus no vaccine, 5,545 fewer QALYs lost and a societal cost-savings of &5.4 million. The number needed to vaccinate to prevent one HZ case was estimated to be 9. HSCT population results were shown to be robust in sensitivity and threshold analyses. In scenario analyses, RZV was cost saving for renal transplant recipients. Incremental cost-effectiveness ratios for other IC populations were &33,268 per QALY gained for human immunodeficiency virus, &67,682 for breast cancer, and &95,972 for Hodgkin lymphoma.ConclusionResults suggest that RZV is a cost-effective option for vaccinating US IC adults for the prevention of HZ and associated complications.Disclosures Desmond Curran, PhD, The GSK group of companies (Employee, Shareholder) Ahmed Salem, MSc, The GSK group of companies (Employee) Stéphane Lorenc, NA, GSK group of companies (Consultant) Brandon Patterson, PharmD, PhD, GSK group of companies (Shareholder) Justin Carrico, BS, GSK group of companies (Consultant)RTI Health Solutions (Employee) Katherine A. Hicks, MS, BSPH, GSK group of companies (Consultant)RTI Health Solutions (Employee) Elizabeth M. La, PhD, The GSK group of companies (Employee, Shareholder) Sara Poston, PharmD, The GSK group of companies (Employee, Shareholder) Christopher F. Carpenter, MD, MHSA, GSK group of companies (Consultant)

Differences of Human Cytomegalovirus Strains in Recipients of Allogeneic Hematopoietic Stem Cells before and after Transplantation

Background. Human cytomegalovirus (HCMV) is a ubiquitous viral infection of worldwide distribution. This virus is the most significant infectious cause of congenital disease, an important opportunist in the immunocompromised hosts, such as allogeneic hematopoietic stem cells transplantation (allo-HSCT) recipients (Mokarski E.S.,2013). If seropositive recipient develops HCMV infection after allo-HSCT, it is usually unknown whether it is a reactivation of endogenous HCMV or a reinfection by a new exogenous HCMV strain. The impact of genetic diversity of HCMV on its pathogenesis has not been well evaluated by now. However, the emerging data indicate a possible correlation: the viral load and the course of the infection were different in AIDS patients with different HCMV genotypes (Renzette, 2015). The estimation of a possible link between viral genotype and probability of HCMV infection occurrence is relevant. Very little data on difference in HCMV genotypes within one patient before and after allo-HSCT is available.The aim. The aim of this study was the identification of difference in HCMV UL139 gene sequences before and after the allo-HSCT.Materials and Methods. Patients: 13 allo-HSCT recipients (5 ALL, 3 AML, 3 CML, 1 AA, 1 lymphoma of the mantle) were enrolled in the study, male/female 6/7; median age was 27 (22-49) years. Patients' blood samples were collected within 6 month before and 6 month after transplantation and tested for the HCMV DNA by PCR. Positive samples were sequenced by Sanger inside the UL139 (putative membrane gp gene) region for genotyping. Sequences within one patient before and after transplantation were compared by BLAST (Basic Local Alignment Search Tool) software.Results and discussion. Sequencing was successfully completed only in samples of 7 patients (pts), probably due to low concentration of the viral DNA in the samples or other technical issues. The comparison of sequences showed (see table) that 3 out of 7 pts had reactivation of endogenous virus, because sequences exhibited 100% match. Another 2 out of 7 patients' sequences showed about 88% match. This indicates change in genotype to phylogenetically closest one. The rest 2 pts did not show any similarity in sequences at all which definitely points to reinfection after allo-HSCT. Data obtained are similar to a recent study by Zawilinska (Zawilinska B, 2016), which appeals that reinfection occurs slightly more often than reactivation. Data analys showed that reactivation was detected in patients with AML, reinfection in patients with ALL. Average period before reactivation occurrence was 27 days and before reinfection occurrence - 111 days. Statistical reliability cannot be obtained due to patients' number paucity. The genotyping of patients' HCMV by comparison of sequences with known genotypes of the UL139 gene from GenBank® revealed that before transplantation HCMV genotype in 3 patients had a strong resemblance to genotype 2, another 2 patients had genotype close to the genotype 5, and 1 patient had genotype 1. After transplantation genotype 2 became dominant and was identified in 6 out of 7 patients (see table).Conclusions. The conducted study shows that HCMV infection after allo-HSCT may be the result of both reactivation of endogenous virus and reinfection by exogenous strain. Reactivation was detected in patients with AML only, reinfection - in patients with ALL only. Reactivation developed earlier than reinfection (27 days versus 111 days). The chosen method allowed us to detect several mononucleotide substitutions in sequences, what can be useful in cases when no evident change of genotype happened after allo-HSCT. There are several possible explanations of the occurrence of reinfection: possible transmission from the outer environment or reactivation of a minor genotype if 2 or more HCMV genotypes originally had taken place. Further studies are required for more reliable conclusions. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

#50: Cytomegalovirus Retinitis Among Pediatric Hematopoietic Stem Cell and Solid Organ Transplantation Recipients: A Contemporary Review

Abstract Background Cytomegalovirus infection can cause significant morbidity and mortality after transplantation. Cytomegalovirus retinitis (CMVR) can be a major complication of tissue invasive CMV disease in transplant recipients. There are little data regarding the contemporary incidence and outcomes of CMVR among pediatric transplant recipients. Methods We performed a retrospective cohort analysis of allogeneic hematopoietic (allo-HCT) and solid organ transplant (SOT) recipients who received medical care at Nationwide Children’s Hospital (NCH) from 1/1/10–11/30/20 and had a diagnosis of CMVR to describe the incidence, timing post-transplant, ocular manifestations, management, and outcomes. Basic demographic and clinical data, pre-transplant donor/recipient CMV serostatus, and post-transplant CMV infection data were collected. Graft-specific CMV surveillance and prophylaxis strategies were performed according to NCH hospital guidelines. During the study period, quantitative plasma CMV PCR assays included copies/mL (2010–2013) and WHO international standard IU/mL (2013–2020). Results During the 10-year study period, 347 patients underwent allo-HCT (N=214) or SOT (N=133; heart N=46, liver N=36, kidney N= 52; 1 patient had concomitant kidney and liver transplantation); median age was 8.6 years [range 0.1–25.9] and 198 (56.5%) were male. In total, 98 patients had CMV DNAemia post-transplant, and CMVR was diagnosed in 3 (HCT=2, SOT=1), for an overall CMVR incidence of 0.86% among all transplant recipients and occurring in 3% of patients with CMV DNAemia. No CMVR was diagnosed in patients without CMV DNAemia. An ophthalmologic examination was performed in 58 (59%) of patients with any DNAemia compared with 67 (27%) of patients without DNAemia. CMVR was diagnosed on funduscopic examination a median of 183 days [range 34–512] post-transplant based on visual symptomatology (N=2) or by routine eye screening prompted by DNAemia (N=1). CMV DNAemia at the time of CMVR was 1,463 copies/mL, 3,000, and 14,204 IU/mL; all patients had prolonged (&amp;gt;3 months) CMV detection before CMVR. One SOT recipient had concomitant pathology confirming CMV gastrointestinal tract disease. Two of the 3 CMVR cases occurred in the setting of genotypic UL94 CMV resistance mutations (A594V, H520Q)(Figure 1). Two patients were already receiving CMV antiviral therapy (maribavir N=1; valganciclovir=1) at the time of CMVR diagnosis. After the CMVR diagnosis, all patients were prescribed systemic foscarnet. Adjunctive therapies included concurrent intravitreal antiviral therapy (ganciclovir N=1; foscarnet N=1) and adoptive immunotherapy with CMV antiviral specific T-cells (N=1, HCT). Improvement of ocular symptoms occurred in 2 patients at 15 and 20 days after starting targeted CMV antiviral therapy; one patient developed permanently impaired vision. Conclusion CMVR remains as an important complication in transplant recipients. Although CMVR incidence was low in our cohort of transplant recipients, it occurred most frequently in cases of CMV resistance, prolonged DNAemia, and led to permanent visual impairment in 1 of 3 patients. The development of resistant CMV may have a role in the occurrence, progression, and severity of CMVR. Additional pediatric-specific data are needed to better characterize CMVR and inform optimal prevention strategies.

Central Nervous System Infections in Immunocompromised Patients.

Purpose of ReviewThis article reviews current epidemiologic trends, clinical presentations, and diagnostic strategies for central nervous system (CNS) infections in human immunodeficiency virus-negative (HIV) patients immunocompromised by their underlying disease or by receipt of immunosuppressive or immunomodulating therapies. Three patient groups are considered: (1) cancer patients; (2) hematopoietic or solid organ transplantation recipients; and (3) patients with autoimmune or inflammatory conditions requiring therapies that alter the host immune response.Recent FindingsClinical presentations, associated neuroimaging, and cerebrospinal fluid (CSF) abnormalities differ between immunocompromised and immunocompetent patients. Infections can trigger the emergence of neurotropic antibodies or inflammatory conditions due to treatment with cancer immunotherapies. Unbiased metagenomic assays to identify obscure pathogens help clinicians navigate the increasing range of conditions affecting the growing population of patients with altered immunity.SummaryAwareness of clinical presentations and disease and drug-specific risks is important for early diagnosis and intervention in these often life-threatening infections and their noninfectious mimes.

427 - Invasive Aspergillosis Remains Associated with High Mortality in Hematopoietic Transplant Recipients in the Current Era

427 - Invasive Aspergillosis Remains Associated with High Mortality in Hematopoietic Transplant Recipients in the Current Era

Broad Virus Detection and Variant Discovery in Fecal Samples of Hematopoietic Transplant Recipients Using Targeted Sequence Capture Metagenomics.

Pediatric allogeneic hematopoietic stem cell transplantation (HSCT) patients often suffer from gastro-intestinal (GI) disease caused by viruses, Graft-versus-Host Disease (GVHD) or a combination of the two. Currently, the GI eukaryotic virome of HSCT recipients remains relatively understudied, which complicates the understanding of its role in GVHD pathogenicity. As decisions regarding immunosuppressive therapy in the treatment of virus infection or GVHD, respectively, can be completely contradicting, it is crucial to better understand the prevalence and relevance of viruses in the GI tract in the HSCT setting. A real time PCR panel for a set of specific viruses widely used to diagnose the most common causes of GI viral gastroenteritis is possibly insufficient to grasp the full extent of viruses present. Therefore, we applied the targeted sequence capture method ViroCap to residual fecal samples of 11 pediatric allogeneic HSCT recipients with GI symptoms and a suspicion of GVHD, to enrich for nucleic acids of viruses that are known to infect vertebrate hosts. After enrichment, NGS was applied to broadly detect viral sequences. Using ViroCap, we were able to detect viruses such as norovirus and adenovirus (ADV), that had been previously detected using clinical diagnostic PCR on the same sample. In addition, multiple, some of which clinically relevant viruses were detected, including ADV, human rhinovirus (HRV) and BK polyomavirus (BKV). Interestingly, in samples in which specific PCR testing for regular viral GI pathogens did not result in a diagnosis, the ViroCap pipeline led to the detection of viral sequences of human herpesvirus (HHV)-7, BKV, HRV, KI polyomavirus and astrovirus. The latter was an only recently described variant and showed extensive sequence mismatches with the applied real time PCR primers and would therefore not have been detected if tested. Our results indicate that target enrichment of viral nucleic acids through ViroCap leads to sensitive and broad possibly clinically relevant virus detection, including the detection of newer variants in clinical HSCT recipient samples. As such, ViroCap could be a useful detection tool clinically, but also in studying the associations between viral presence and GVHD.

A 9-Year-Old Male with Barth Syndrome and a Cardiac Transplant Presenting with Hyperviscosity Syndrome Caused By EBV-Negative Plasmacytic PTLD

Posttransplant lymphoproliferative disorders (PTLD) are a spectrum of disorders characterized by lymphoid or plasmacytic proliferation secondary to extrinsic immunosuppression in solid organ transplant (SOT) or hematopoietic transplant recipients. According the 2016 revision of World Health Organization (WHO) classification, PTLD ranges from early lesion (mononucleosis-like) lymphoid hyperplasia or plasmacytic hyperplasia, polymorphic, monomorphic to classical Hodgkin lymphoma PTLD (Swerdlow et. al. Blood 2016). The incidence of PTLD in the pediatric population is closely associated with the type of transplanted organ, with the highest incidence in lung and small bowel transplant recipients due to chronic, iatrogenic immunosuppression. While Epstein-Barr Virus (EBV) is the key driver of abnormal lymphocytic proliferation in the majority of PTLDs, EBV-negative PTLD is a distinct subtype. We hereby report a 9-year-old boy with Barth syndrome, a rare genetic syndrome caused by a TAZ mutation, characterized by dilated cardiomyopathy, skeletal myopathy, neutropenia, and short stature. He required a heart transplant for left ventricular non-compaction cardiomyopathy at 11 months of age and presented with lower GI bleeding, acute-onset anemia, somnolence, retinal hemorrhages, and increased serum viscosity eight years post transplant. Workup was significant for hyperimmunoglobulinemia with elevated IgA and IgG, and serum protein electrophoresis (SPEP) showed two monoclonal bands (IgA Lambda and IgG Kappa) and an M spike. He was treated with plasmapheresis, and his symptoms improved significantly. Further workup with PET/CT scan showed diffuse lymphadenopathy of cervical, mediastinal, axillary, abdominal, and inguinal lymph nodes. Axillary lymph node biopsy was done, demonstrating a nondestructive morphology with an increase in plasma cells expressing excess lambda light chain and IgA; these abnormal cells were CD20 negative and CD138 positive, suggesting a clonal process. Cytogenetic fluorescence in situ hybridization (FISH) showed loss of TP53. Serum EBV detection by PCR and EBER staining by immunohistochemistry (IHC) on lymph node pathology were negative. Bone marrow biopsy showed a hypocellular marrow with trilineage hematopoiesis and 5-10% CD138 positive plasma cells. Combined, these studies were consistent with the diagnosis of early onset, nondestructive, plasmacytic PTLD. The patient was treated with a multiple myeloma-type therapy with dexamethasone and bortezomib (Short et. al. J Pediatr Hematol Oncol 2016), in addition to reduced immunosuppression consisting of low dose tacrolimus. Repeat PET/CT scan after 2 cycles of therapy showed resolution of previous PET-avid lesions. Stem cell collection was performed after 3 cycles in case of relapsed or recurrent disease. He completed 5 cycles of therapy with no complications. Unfortunately, the patient's end of treatment PET/CT scan was significant for a new mediastinal mass and multiple intraabdominal lymph nodes. Lymph node biopsy showed a lymphoplasmacytic infiltrate, which was IgA and lambda positive. The cells showed plasmacytoid features, but in contrast to the initial biopsy at diagnosis, there was marked CD20 positivity (image attached). This recurrence was most suggestive of a marginal zone lymphoma like PTLD (Galera et. al. Am J Surg Pathol 2020). He was initiated on therapy with rituximab and bendamustine. He is currently status post 2 treatment cycles and doing well. We continue to discuss the utility of autologous bone marrow transplant in this case, although the risks and benefits will have to be weighed carefully in a child who is prone to develop infections and complications from Barth Syndrome. We would like to share this case of EBV negative, plasmacytic PTLD with relapsed marginal zone lymphoma type PTLD to highlight the heterozygous pathologies of PTLD in children, and to share our experience of treating in the absence of standard protocol due to the rarity of this diagnosis. Figure Disclosures No relevant conflicts of interest to declare.

Enhanced coping and self-efficacy in caregivers of hematopoietic stem cell transplant (HCT) recipients: Identifying mechanisms of a multimodal psychosocial intervention.

12122 Background: A brief multimodal psychosocial intervention (BMT-CARE) for caregivers of HCT recipients demonstrated promising efficacy for improving caregiver quality of life (QOL), mood, coping skills, and self-efficacy. We examined whether improvements in coping and self-efficacy mediated the intervention effects on QOL and mood. Methods: We conducted a randomized clinical trial of BMT-CARE for caregivers of patients undergoing autologous or allogeneic HCT at a single institution. Caregivers were randomly assigned to BMT-CARE or usual care. BMT-CARE was tailored to the HCT trajectory and integrated treatment-related education and self-care with cognitive-behavioral skills and caregiving-specific strategies to promote coping. Caregivers completed self-report measures of QOL (CareGiver Oncology QOL), depression and anxiety symptoms (Hospital Anxiety and Depression Scale), coping skills (Measure of Current Status), and self-efficacy (Cancer Self-Efficacy Scale-Transplant) at enrollment and 60 days post-HCT. We used causal mediation regression models to examine whether changes in coping and self-efficacy mediated intervention effects on QOL, depression and anxiety symptoms. Results: Caregivers randomized to BMT-CARE reported improved self-efficacy (adjusted means: 156.20 vs. 147.06, P=0.023) and coping skills (adjusted means: 36.54 vs. 25.41, P&lt;0.001). Improved coping and self-efficacy partially mediated the intervention effects on 60-day QOL (indirect effect=6.93, SE=1.85, 95% CI [3.71, 11.05]). Similarly, improved coping and self-efficacy partially mediated reductions in 60-day depression and anxiety symptoms (indirect effect depression=-1.19, SE=0.42, 95% CI [-2.23, -0.53]; indirect effect anxiety=-1.46, SE=0.55, 95% CI [-2.52, -0.43]). Combined improvements in coping and self-efficacy accounted for 67%, 80%, and 39% of the total intervention effect on QOL and depression and anxiety symptoms, respectively. Conclusions: A brief multimodal intervention for caregivers of HCT recipients may improve QOL and mood by enhancing coping skills and self-efficacy. These findings offer important insights into the mechanisms by which caregiver-directed interventions may enhance caregiver QOL and reduce their psychological distress.

Effect of Denosumab on Bone Mineral Density of Hematopoietic Stem Cell Transplantation Recipients.

Purpose Denosumab is a monoclonal antibody that prevents the development of osteoclasts. The effect of denosumab in solid organ transplant recipients has been elucidated, but its effect in haematopoietic stem cell transplantation recipients has not been studied yet. The aim of this study was to determine the effectiveness and safety of denosumab in haematopoietic stem cell transplantation recipients. Methods We retrospectively evaluated 33 female patients with osteoporosis (mean age 52.6 ± 9.8 years) following allogeneic haematopoietic stem cell transplantation. Patients were treated with denosumab every 6 months for 12 months. Changes in bone mineral density were evaluated for denosumab-treated patients in a 12-month interval after the first administration of denosumab. Results Significant increases in bone mineral density were observed in all measured skeletal sites including 4.39 ± 6.63% in the lumbar spine (p=0.014), 3.11 ± 7.69% in the femoral neck (p=0.048), and 1.97 ± 6.01% in the total hip (p=0.138). The bone turnover marker serum cross-linked C-terminal telopeptide of type 1 collagen was decreased at 18 months (−51.6 ± 17.6%, p < 0.001). No serious symptomatic hypocalcaemia was observed. Serious adverse drug reactions requiring drug discontinuation were not observed. Conclusion Denosumab improved bone mineral density in haematopoietic stem cell transplantation recipients. The use of denosumab could be a good therapeutic option without causing severe adverse effects in recipients of haematopoietic transplantation.

Challenges and Unmet Oncofertility Needs in Hematopoietic Stem Transplant Recipients in a Middle-Income Nation

Lack of fertility assessment (FA) and counsel (FC) has a negative impact on quality of life in cancer survivors. Cryopreservation (CP) offers a possibility of future progeny in both males and females. Hematopoietic stem cell transplant (HSCT) recipients are a high-risk group, whose increased risk of relapse limits time off of therapy for CP. Our aim was to evaluate trends in pre and post-HSCT gonadal dysfunction (GD) in HSCT recipients in a referral center in Latin America.This is a retrospective single-center study that included patients who underwent HSCT at our institution from June 2000 to May 2018, whose baseline diagnosis was established at <45 years of age.Inclusion criteria were met by 213 patients. Median age at diagnosis was 26 years and 64.8% were male. 70.4% were of low socioeconomic (SE) status (monthly income <180 USD). Baseline diagnosis was hematologic in 84%. In 81.2% of patients, systemic cytotoxic therapy was required, with a median time to initiation of one day. Gonadal toxicity risk profile (GTP) of therapy was intermediate/high in 26.6% (Figure 1).Median age at HSCT was 29 years. HSCT was autologous in 54.9%. Median time from diagnosis to HSCT was 15 months and was 3 months from last therapy to HSCT. Conditioning regimen was myeloablative (MA) in 87.1% (Figure 1).Full pre-HSCT biochemical FA was available in 71.8% of patients (n=153) being consistent with GD in 22.9% (n=35). Female gender was associated with pre-HSCT GD (p<0.001), despite males receiving regimens of higher GTP (p<0.001). FC was performed in 55.4% (n=118) of patients, more so in women than men (p<0.001). Only 3.3% (n=7) of the cohort completed CP (Figure 2).At 6 months post-HSCT 193 patients were evaluable. Only 47.7% (n=92) had full FA. GD was present in 47.8% (n=44) and was related to female gender (p=0.03). Within females increased median concentration of FSH (p<0.001) and LH (p<0.001), lower median concentration of estradiol (p=0.005), and an association of GD with MA regimens (p=0.002) were observed. In males only FSH median concentration (p=0.002) was altered and GD was related to germ cell tumor (GCT) diagnosis (p=0.019) (Figure 2/3).Despite the young age of our cohort few patients received FC. CP was almost null due to SE constrains, accessibility, and limited therapy-free time. Only 1 of every 4 patients had biochemical evidence suggestive of GD pre-HSCT. Greater care must be taken to allocate intervals for CP while weighing risk of relapse.Factors related to GD were female gender, MA regimens in females, and GCT in males; possibly evidencing the role of the blood-testis barrier in decreasing intragonadal drug concentrations.The reduced proportion of post-HSCT FA evidences lack of awareness among clinicians.Our results show the great need of multidisciplinary approaches in HSCT recipients and resource-stratified guidelines to select those with the greatest potential to benefit from a fertility perspective. Lack of fertility assessment (FA) and counsel (FC) has a negative impact on quality of life in cancer survivors. Cryopreservation (CP) offers a possibility of future progeny in both males and females. Hematopoietic stem cell transplant (HSCT) recipients are a high-risk group, whose increased risk of relapse limits time off of therapy for CP. Our aim was to evaluate trends in pre and post-HSCT gonadal dysfunction (GD) in HSCT recipients in a referral center in Latin America. This is a retrospective single-center study that included patients who underwent HSCT at our institution from June 2000 to May 2018, whose baseline diagnosis was established at <45 years of age. Inclusion criteria were met by 213 patients. Median age at diagnosis was 26 years and 64.8% were male. 70.4% were of low socioeconomic (SE) status (monthly income <180 USD). Baseline diagnosis was hematologic in 84%. In 81.2% of patients, systemic cytotoxic therapy was required, with a median time to initiation of one day. Gonadal toxicity risk profile (GTP) of therapy was intermediate/high in 26.6% (Figure 1). Median age at HSCT was 29 years. HSCT was autologous in 54.9%. Median time from diagnosis to HSCT was 15 months and was 3 months from last therapy to HSCT. Conditioning regimen was myeloablative (MA) in 87.1% (Figure 1). Full pre-HSCT biochemical FA was available in 71.8% of patients (n=153) being consistent with GD in 22.9% (n=35). Female gender was associated with pre-HSCT GD (p<0.001), despite males receiving regimens of higher GTP (p<0.001). FC was performed in 55.4% (n=118) of patients, more so in women than men (p<0.001). Only 3.3% (n=7) of the cohort completed CP (Figure 2). At 6 months post-HSCT 193 patients were evaluable. Only 47.7% (n=92) had full FA. GD was present in 47.8% (n=44) and was related to female gender (p=0.03). Within females increased median concentration of FSH (p<0.001) and LH (p<0.001), lower median concentration of estradiol (p=0.005), and an association of GD with MA regimens (p=0.002) were observed. In males only FSH median concentration (p=0.002) was altered and GD was related to germ cell tumor (GCT) diagnosis (p=0.019) (Figure 2/3). Despite the young age of our cohort few patients received FC. CP was almost null due to SE constrains, accessibility, and limited therapy-free time. Only 1 of every 4 patients had biochemical evidence suggestive of GD pre-HSCT. Greater care must be taken to allocate intervals for CP while weighing risk of relapse. Factors related to GD were female gender, MA regimens in females, and GCT in males; possibly evidencing the role of the blood-testis barrier in decreasing intragonadal drug concentrations. The reduced proportion of post-HSCT FA evidences lack of awareness among clinicians. Our results show the great need of multidisciplinary approaches in HSCT recipients and resource-stratified guidelines to select those with the greatest potential to benefit from a fertility perspective. Figures 1, Figure 2, Figure 3.Figure 2Fertility & Gonadal Dysfunction Evaluation.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Figure 3Factors affecting gonadal dysfunction.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Acute Kidney Injury in Allogeneic Hematopoietic Transplant Recipients

<h3>Background</h3> The reported incidence of acute kidney injury (AKI) after allogeneic hematopoietic cell transplantation (allo-HCT) varies from 10 to 73%. The association between GVHD, calcineurin inhibitors (CNIs) and risk for kidney injury remains controversial. We sought to describe the incidence of AKI and identify modifiable risk factors in large cohort of patients undergoing allo-HCT in our institution. <h3>Methods</h3> All consecutive patients undergoing allo-HCT from 2014 to 2017 in our institution were included. Pre-HCT variables including patient and graft characteristics, as well as post-HCT variables, including nephrotoxic medication exposure, ICU admission, and CNI levels were analyzed in association with AKI. AKI was defined using KDIGO criteria, grades 1, 2 and 3, through post-transplant day 100. Severe AKI was defined as grades 2 or 3. Differences across groups were assessed using either Wilcoxon rank-sum tests or Fisher's exact tests. AKI risk factors were estimated using cause-specific Cox proportional hazards regression. <h3>Results</h3> A total of 616 patients underwent allo-HCT during the study period. Median age was 58 (19-79) years, 59% male, 83% Caucasian. Indication for HCT was leukemia in 49%, myelodysplastic syndrome in 16%, and lymphoma in 17%. Median baseline creatinine was 0.8 (0.3-2.7) mg/dL. Median age-adjusted HCT-comorbidity index was 3 (range 0-9). Median baseline albumin was 3.5 (IQR 3.3-3.8) mg/dL and BMI 27.2 (IQR 23.8-30.8). Incidence of acute GVHD was 47%, and 60 patients had severe (grades 3-4) GVHD. Bacteremia occurred in 19% of patients. Amphotericin preceded max-grade AKI in 3.1%, cidofovir in 0.8%, and Foscarnet in 4.4% of patients. Median tacrolimus level preceding AKI was 7.88 (range 4.2-23.2) mg/dL. By day 100 post-HCT, 403 (65.4%) had any AKI, 220 (35.7%) patients had grade 1 AKI, 119 (19.3%) grade 2 AKI, and 64 (10.4%) grade 3 AKI; 19 (3.1%) required hemodialysis. Median time to AKI was 17 (IQR 8-35) days, and median time to max-grade AKI was 31 (IQR 13-53) days. Ex vivo CD34-selected HCT patients had a lower risk for AKI, hazard ratio 0.46 (0.35-0.62), p<0.001 (Table 1). <h3>Conclusion</h3> AKI in patients undergoing allo-HCT remains a major concern, affecting 65.4% of patients, with grade 2 and 3 AKI occurring in 19.3% and 10.4%, respectively. Patients receiving CNIs including tacrolimus have a significantly higher risk for AKI, whereas patients undergoing CD34-selected allo-HCT have a lower risk of AKI. The effect of AKI after HCT on long-term kidney function requires further prospective study.

T-cells immune response controls the high incidence of adenovirus infection in adult allogenic hematopoietic transplantation recipients

T-cells immune response controls the high incidence of adenovirus infection in adult allogenic hematopoietic transplantation recipients