Impact of prophylaxis with rituximab on EBV-related complications after allogeneic hematopoietic cell transplantation in children.

Background: Children undergoing allo-HCT are at high risk of EBV-related complications. The objective of the study was to analyze the impact of prophylactic post-transplant rituximab on EBV infection and EBV-PTLD in children after allo-HCT, to determine the risk factors for the development of EBV infection and EBV-PTLD and to determine their outcomes. Additionally, the impact of EBV-driven complications on transplant outcomes was analyzed. Methods: Single center retrospective analysis of EBV-related complications in pediatric population undergoing allo-HCT, based on strategy of prophylaxis with rituximab. Overall 276 consecutive children, including 122 on prophylaxis, were analyzed for EBV-driven complications and transplant outcomes. Results: Prophylaxis with rituximab resulted in significant reduction of EBV infection (from 35.1% to 20.5%; HR=2.7; p<0.0001), and EBV-PTLD (from 13.0% to 3.3%; HR=0.23; p=0.0045). A trend for improved survival was also observed (HR=0.66; p=0.068), while non-relapse mortality was comparable in both cohorts. The peak value of viral load was a risk factor in the development of EBV-PTLD: 10-fold higher peak viral load in comparison to the baseline 104 copies/mL, caused a 3-fold (HR=3.36; p<0.001) increase in the risk of EBV-PTLD. Rituximab treatment was effective as a preemptive therapy in 91.1%, and in 70.9% in EBV-PTLD. Patients who developed PTLD had dismal 5-year overall survival (29% vs 60%; p<0.001), and an increased risk of relapse (72% vs 35%; p=0.024). Conclusions: Rituximab for prophylaxis of EBV infection and EBV-PTLD was highly effective in pediatric population. Treatment of EBV-PTLD was successful in 70%, however the occurrence of EBV-PTLD was associated with an increased risk of relapse of primary malignant disease.

[Clinical analysis of 18 children with aggressive mature B-cell lymphoma after liver transplantation].

Objective: To summarize the clinical characteristics, prognostic factors and treatment outcomes of childhood aggressive mature B-cell lymphoma after liver transplantation. Methods: This retrospective study included 18 children with newly diagnosed aggressive mature B-cell lymphoma after liver transplantation and treated from June 2018 to June 2022 in the Department of Hematology and Oncology of Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine. Clinical characteristics, treatment and outcomes of patients at last evaluation were analyzed. Overall survival (OS) and event free survival (EFS) rates were calculated by Kaplan-Meier method and Log-Rank analysis was performed to find factors of poor prognosis. Results: Among all 18 patients, there were 6 males and 12 females, and the age of onset was 40 (35, 54) months. The interval from transplant to tumor diagnosis was 21 (17, 35) months and 5 patients had early onset disease (<1 year since transplant). Seventeen patients had abdominal lesions. Diarrhea, vomiting and abdominal masses were the main clinical manifestations. All patients were Epstein-Barr virus (EBV) related posttransplant lymphoproliferative disorders (PTLD). One patient received individualized therapy due to critical sick at diagnosis, and the remaining 17 patients received CP (cyclophosphamide, methylprednisolone plus rituximab) and (or) modified EPOCH (prednisone, etoposide, doxorubicin, vincristine, cyclophosphamide plus rituximab) regimens. Of all 18 patients, 15 cases got complete response, 2 cases got partial response, 1 patient died of severe infection. The 2-year OS and EFS rates of 18 patients were (94±5)% and (83±8)%, respectively. None of age, gender or early onset disease had effect on OS and EFS rates in univariate analysis (all P>0.05). Conclusions: The symptoms of PTLD were atypical. Close surveillance of EBV-DNA for patients after liver transplantation was crucial to early stage PTLD diagnosis. CP or modified EPOCH regimen was efficient for pediatric patients with aggressive mature B cell lymphoma after liver transplantation.

The impact of induction therapy on the risk of posttransplant lymphoproliferative disorder in adult kidney transplant recipients with donor-recipient serological Epstein-Barr virus mismatch.

Posttransplant lymphoproliferative disorder (PTLD) poses a significant concern in Epstein-Barr virus (EBV)-negative patients transplanted from EBV-positive donors (EBV R-/D+). Previous studies investigating the association between different induction agents and PTLD in these patients have yielded conflicting results. Using the Organ Procurement and Transplant Network database, we identified EBV R-/D+ patients >18 years of age who underwent kidney-alone transplants between 2016 and 2022 and compared the risk of PTLD with rabbit antithymocyte globulin (ATG), basiliximab, and alemtuzumab inductions. Among the 6620 patients included, 64.0% received ATG, 23.4% received basiliximab, and 12.6% received alemtuzumab. The overall incidence of PTLD was 2.5% over a median follow-up period of 2.9 years. Multivariable analysis demonstrated that the risk of PTLD was significantly higher with ATG and alemtuzumab compared with basiliximab (adjusted subdistribution hazard ratio [aSHR] = 1.98, 95% confidence interval [CI] 1.29-3.04, P = .002 for ATG and aSHR = 1.80, 95% CI 1.04-3.11, P = .04 for alemtuzumab). However, PTLD risk was comparable between ATG and alemtuzumab inductions (aSHR = 1.13, 95% CI 0.72-1.77, P = .61). Therefore, the risk of PTLD must be taken into consideration when selecting the most appropriate induction therapy for this patient population.

Reactivation of Epstein-Barr virus among intensive care patients: a prospective observational study.

PURPOSE: Herpesvirus reactivation has been documented among patients in the intensive care unit (ICU) and is associated with increased morbidity and mortality, particularly for cytomegalovirus (CMV). Epstein-Barr virus (EBV) has been poorly studied despite >95% of the population being seropositive. Our preliminary study suggested an association between EBV reactivation and increased morbidity and mortality. This study aimed to investigate this association among patients admitted to the ICU. METHODS: In this multicenter prospective study, polymerase chain reaction was performed to quantify EBV in patients upon ICU admission and then twice a week during their stay. Follow-up was 90 days. RESULTS: The study included 129 patients; 70 (54.3%) had EBV reactivation. On day 90, there was no difference in mortality rates between patients with and without reactivation (25.7% vs 15.3%, p = 0.22). Patients with EBV reactivation at admission had increased mortality compared with those without reactivation and those with later reactivation. EBV reactivation was associated with increased morbidity. Patients with EBV reactivation had fewer ventilator-free days at day 28 than those without reactivation (18 [1-22] vs. 21 days [5-26], p = 0.037) and a higher incidence of acute respiratory distress syndrome (34.3% vs. 17%, p = 0.04), infections (92.9% vs. 78%, p = 0.03), and septic shock (58.6% vs. 32.2%, p = 0.004). More patients with EBV reactivation required renal replacement therapy (30% vs. 11.9%, p = 0.02). EBV reactivation was also associated with a more inflammatory immune profile. CONCLUSION: While EBV reactivation was not associated with increased 90-day mortality, it was associated with significantly increased morbidity.

Safety and efficacy of a reduced frequency viral monitoring strategy for Epstein-Barr virus, cytomegalovirus, and BK polyomavirus post-kidney transplant: A quality assurance initiative.

BACKGROUND: There is variability in recommended viral monitoring protocols after kidney transplant. In response to increased demand for laboratory testing during the COVID-19 pandemic, the Transplant Manitoba Adult Kidney Program updated its monitoring protocols for cytomegalovirus (CMV), Epstein-Barr virus (EBV), and BK polyomavirus (BKV) to a reduced frequency. METHODS: This single-center nested case-control study evaluated 252 adult kidney transplant recipients transplanted from 2015 to 2021, with the updated protocols effective on March 19th 2020. Cases included recipients transplanted after the protocol update who developed CMV, EBV, and BKV DNAemia and were matched to controls with DNAemia transplanted prior to the protocol update. The primary outcome was the difference in maximum DNA load titers between cases and matched controls. Secondary outcomes included time to initial DNAemia detection and DNAemia clearance. Safety outcomes of tissue-invasive viral disease were described. RESULTS: There were 216 recipients transplanted preupdate and 36 recipients postupdate. There was no difference between cases and controls in maximum or first DNA load titers for EBV, CMV, or BKV. Cases experienced earlier EBV DNAemia detection (26 (IQR 8, 32) vs. 434 (IQR 96, 1184) days, p = .005). Median follow-up was significantly longer for recipients transplanted preupdate (4.3 vs. 1.3 years, p < .0001). After adjusting for follow-up time, there was no difference in DNAemia clearance or tissue-invasive viral disease. CONCLUSION: Our findings suggest that reduced frequency viral monitoring protocols may be safe and cost-effective. This quality assurance initiative should be extended to detect longer-term and tissue-invasive disease outcomes.

Tabelecleucel for allogeneic haematopoietic stem-cell or solid organ transplant recipients with Epstein-Barr virus-positive post-transplant lymphoproliferative disease after failure of rituximab or rituximab and chemotherapy (ALLELE): a phase 3, multicentre, open-label trial.

BACKGROUND: Survival in Epstein-Barr virus (EBV)-positive post-transplant lymphoproliferative disease following haematopoietic stem-cell transplant (HSCT) or solid organ transplant (SOT) is poor after failure of initial therapy, indicating an urgent need for therapies for this ultra-rare disease. With recent EU marketing authorisation, tabelecleucel is the first off-the-shelf, allogeneic, EBV-specific T-cell immunotherapy to receive approval for treatment of relapsed or refractory EBV-positive post-transplant lymphoproliferative disease. We aimed to determine the clinical benefit of tabelecleucel in patients with relapsed or refractory EBV-positive post-transplant lymphoproliferative disease following HSCT or SOT. METHODS: In this global, multicentre, open-label, phase 3 trial, eligible patients (of any age) had biopsy-proven EBV-positive post-transplant lymphoproliferative disease, disease that was relapsed or refractory to rituximab after HSCT and rituximab with or without chemotherapy after SOT, and partially HLA-matched and appropriately HLA-restricted tabelecleucel available. Patients received tabelecleucel administered intravenously at 2 × 106 cells per kg on days 1, 8, and 15 in 35-day cycles and are assessed for up to 5 years for survival post-treatment initiation. The primary endpoint was objective response rate. All patients who received at least one dose of tabelecleucel were included in safety and efficacy analyses. This trial is registered with ClinicalTrials.gov, NCT03394365, and is ongoing. FINDINGS: From June 27, 2018, to Nov 5, 2021, 63 patients were enrolled, of whom 43 (24 [56%] male and 19 [44%] female) were included, 14 had prior HSCT, 29 had SOT. Seven (50%, 95% CI 23-77) of 14 participants in the HSCT group and 15 (52%, 33-71) of 29 participants in the SOT group had an objective response, with a median follow-up of 14·1 months (IQR 5·7-23·9) and 6·0 months (1·8-18·4), respectively. The most common grade 3 or 4 treatment-emergent adverse events were disease progression (in four [29%] of 14 in HSCT and eight [28%] of 29 in SOT) and decreased neutrophil count (in four [29%] of 14 in HSCT and four [14%] of 29 in SOT). Treatment-emergent serious adverse events were reported in 23 (53%) of 43 patients and fatal treatment-emergent adverse events in five (12%); no fatal treatment-emergent adverse event was treatment-related. There were no reports of tumour flare reaction, cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, transmission of infectious diseases, marrow rejection, or infusion reactions. No events of graft-versus-host disease or SOT rejection were reported as related to tabelecleucel. INTERPRETATION: Tabelecleucel provides clinical benefit in patients with relapsed or refractory EBV-positive post-transplant lymphoproliferative disease, for whom there are no other approved therapies, without evidence of safety concerns seen with other adoptive T-cell therapies. These data represent a potentially transformative and accessible treatment advance for patients with relapsed or refractory disease with few treatment options. FUNDING: Atara Biotherapeutics.

Open-Label, Multicenter, Randomized, Biomarker-Integrated Umbrella Trial for Second-Line Treatment of Advanced Gastric Cancer: K-Umbrella Gastric Cancer Study.

PURPOSE: This study aimed to screen targeted agents as second-line treatment with a standard-of-care (SOC) controlled umbrella trial design in advanced gastric cancer (AGC). PATIENTS AND METHODS: Patients with HER2-negative AGC from eight Korean cancer centers were screened for druggable targets using immunohistochemistry (IHC) and in situ hybridization, and randomly assigned to the biomarker versus control group at a 4:1 ratio. In the biomarker group, patients were treated with specific targeted agent plus paclitaxel: pan-ERBB inhibitor for epidermal growth factor receptor (EGFR) 2+/3+ patients (afatinib; EGFR cohort), PIK3Cß inhibitor for phosphatase and tensin homolog (PTEN) loss/null patients (GSK2636771; PTEN cohort), and anti-PD-1 inhibitor for PD-L1+, deficient mismatch repair/microsatellite instability-high, or Epstein-Barr virus-related cases (nivolumab; NIVO cohort). NONE cohort in the biomarker group without predefined biomarkers and control group received SOC (paclitaxel with or without ramucirumab). The primary end point was progression-free survival (PFS), and the secondary end points were efficacy and safety. RESULTS: A total of 318 patients were randomly assigned into the control (n = 64) and biomarker (n = 254; EGFR, n = 67; PTEN, n = 37; NIVO, n = 48; NONE, n = 102) groups. Median follow-up was 35 months. Median PFS and overall survival (OS) were 3.7 (95% CI, 3.1 to 4.1) and 8.6 (95% CI, 7.6 to 9.8) months in the biomarker group and 4.0 (95% CI, 3.0 to 4.6) and 8.7 (95% CI, 7.1 to 9.9) months in the control group. Afatinib addition led to marginal survival benefits to patients with EGFR 3+ compared with SOC (PFS, 4.0 v 2.2 months; P = .09), but GSK2636771 did not prolong the survival of patients with PTEN loss. Addition of nivolumab showed a durable survival benefit (median OS, 12.0 v 7.6 months; P = .08). CONCLUSION: Although biomarker group did not show better survival than the control group, IHC-based screening and allocation of patients with AGC to the second-line treatment in an umbrella design were feasible for effective early screening of novel agents.

Treatment of Monomorphic Posttransplant Lymphoproliferative Disorder in Pediatric Solid Organ Transplant: A Multicenter Review.

Posttransplant lymphoproliferative disorder (PTLD) is the most common posttransplant malignancy in children. We reviewed data from 3 Canadian pediatric centers to determine patient characteristics, treatment approaches, and outcomes for children with monomorphic PTLD. There were 55 eligible children diagnosed between January 2001 to December 2021. Forty-eight patients (87.2%) had B-cell PTLD: Burkitt lymphoma (n = 25; 45.4%) and diffuse large B-cell lymphoma (n = 23; 41.2%), the remainder had natural killer (NK)/T-cell lymphoma (n = 5; 9.1%), Hodgkin lymphoma (n = 1;1.8%), or other (n = 1;1.8%). Thirty-nine (82.1%) patients with B-cell PTLD were treated with rituximab and chemotherapy with or without a reduction in immunosuppression (reduced immune suppression). The chemotherapy used was primarily one of 2 regimens: Mature Lymphoma B-96 protocol in 22 patients (56.4%) and low-dose cyclophosphamide with prednisone in 14 patients (35%). Most patients with T/NK-cell lymphoma were treated with reduced immune suppression + chemotherapy (n = 4; 80%). For all patients with monomorphic PTLD, the projected 3-year event-free survival/3-year overall survival was 62% and 77%, respectively. Of the patients, 100% with T/NK-cell PTLD 100% progressed or relapsed and, subsequently, died of disease. For patients with B-cell PTLD, there was no significant difference in outcome between the two main chemotherapy regimens employed.

Epstein-Barr virus reactivation correlates with worse outcomes for patients exposed to hepatitis B virus after haploidentical hematopoietic stem cell transplantation.

Hepatitis B virus (HBV)has a high, chronic infection rate in Asian populations, but only few studies have analyzed the effect of Epstein-Barr virus (EBV) or Cytomegalovirus (CMV) reactivation in patients exposed to HBV after haploidentical hematopoietic stem cell transplantation (haplo-HSCT). This study aimed to assess the clinical outcomes of these patients. We conducted a retrospective research including 61 patients exposed to HBV after undergoing haplo-HSCT. The patients were classified into two groups: the CMV reactivation group and no CMV reactivation group. The results were compared between the two groups using the K-W test for continuous variables, Pearson's chi-square test for categorical variables, Kaplan-Meier curves to estimate overall survival (OS) and leukemia-free survival (LFS), and a Cox proportional hazards model to analyze multivariable influences. The 3-year cumulative HBV reactivation rate was 8.2%. The median duration of HBV reactivation was 16 months (16-22 months) after haplo-HSCT. The CMV reactivation group had a higher cumulative incidence of HBV reactivation than the group without CMV reactivation. The EBV reactivation was substantially higher in the CMV reactivation group compared to that in the no CMV reactivation group (37.0% vs.5.9% respectively; P = 0.002). Furthermore, EBV reactivation was a risk factor for 1-year LFS and 1-year OS. Based on our data, EBV reactivation was related to worse outcomes in patients exposed to HBV after haplo-HSCT, whereas CMV reactivation was not.

Programmed cell death ligand 1 expression associated with subtypes of post-transplant lymphoproliferative disorder among pediatric kidney transplant recipients.

BACKGROUND: Programmed cell death ligand 1 (PD-L1) expression on tumor cells engages the PD-1 receptor on T cells, inhibiting anti-tumor responses. PD-L1 has been detected in cases of post-transplant lymphoproliferative disorder (PTLD) but reports are limited. Here we examine PD-L1 expression and evaluate for clinical correlations. METHODS: Twenty-one cases of PTLD were identified among pediatric kidney transplant recipients at our institution from February 1996 to April 2017. Using paraffin-embedded tissue biopsies, we examined 21 primary tumors for expression using PD-L1 monoclonal antibody performed with PAX5 as a double stain. We scored expression of PD-L1 on lesional B-cells as a percentage of positive cells. Clinical course and outcome were obtained from retrospective chart review. RESULTS: Applying revised 2017 WHO PTLD classification showed five non-destructive, nine polymorphic, and seven monomorphic cases. Average PD-L1 expression based upon PTLD subtype was: non-destructive 11%, polymorphic 43%, and monomorphic 73% (p = .01). Two patients transferred shortly after diagnosis, five received chemotherapy, and three died from PTLD. Among the fatalities, all showed monomorphic PTLD and 90% of lesional B-cells expressed PD-L1. CONCLUSION: In this case series, significant differences in PD-L1 expression were seen among different subtypes, and monomorphic PTLD demonstrated the highest expression. Study of a larger cohort is needed, and if the correlation of PD-L1 expression and PTLD subtype is confirmed, this may highlight the potential utility of checkpoint inhibitor therapy in cases of severe or refractory disease among kidney transplant recipient in whom the risk of allograft loss is acceptable given the option of chronic dialysis.

Haploidentical Cord Blood Transplantation with 8 mg/kg Antithymocyte Globulin as Graft-versus-Host Disease Prophylaxis Compared to Haploidentical Transplantation with 10 mg/kg Antithymocyte Globulin in the Treatment of Acute Leukemia.

Clinical outcomes of the transplantation strategy combined with a haploidentical stem cell graft and an unrelated umbilical cord blood unit (haplo-cord HSCT) with low-dose antithymocyte globulin (ATG) as graft-versus-host disease (GVHD) prophylaxis for the treatment of acute leukemia remains unclear. This study aimed to explore the clinical outcomes of haplo-cord HSCT in acute leukemia patients with the GVHD prevention strategy of 8 mg/kg ATG compared with haploidentical transplantation with 10 mg/kg ATG. A total of 130 patients with acute leukemia who underwent allogeneic HSCT between January 2016 and December 2020 were included in this study, including 70 patients who received haploidentical stem cell grafts and unrelated umbilical cord blood units (haplo-cord HSCT) with 8 mg/kg ATG (haplo-cord-ATG8 group) and haploidentical HSCT with 10 mg/kg ATG (haplo-ATG10 group) in 60 patients. Clinical data were collected and analyzed retrospectively. Patients in the haplo-cord-ATG8 group were significantly older compared with the haplo-ATG10 group (P = .000). Haplo-cord HSCT with reduced ATG to 8 mg/kg results in more rapid neutrophil recovery (P = .036). No between-group differences were observed in platelet recovery or the incidences of Epstein-Barr virus viremia, bloodstream infection, or hemorrhagic cystitis. The rate of grade II-IV acute GVHD by day 100 post-transplantation was higher in the haplo-ATG10 group (27.16% versus 11.48%; P = .033), as was the rate of chronic GVHD at 1 year (14.60% versus 3.36%; P = .048). The rate of cytomegalovirus reaction was higher in the haplo-ATG10 group (48.31% versus 26.30%; P = .022). With a median follow-up of 27.4 months for the haplo-cord-ATG8 group and 27.5 months for the haplo-ATG10 group, overall survival (OS) at 2 years was 79.4% versus 62.8% (P = .005), event-free survival (EFS) was 76.3% versus 55.9% (P = .001), the cumulative incidence of relapse was 10.11% versus 25.97% (P = .164), and nonrelapse mortality (NRM) was 14.33% versus 24.43% (P = .0040). Multivariate analysis identified Center for International Blood and Marrow Transplant Research Disease Risk Index was the sole significant predictor of relapse, NRM, OS, and EFS. Haplo-cord HSCT supported by cord blood with 8 mg/kg ATG as GVHD prophylaxis results in better outcomes compared with haplo-HSCT with 10 mg/kg ATG.

Retrospective study of risk factors for pericardial effusion after haematopoietic stem cell transplantation in children.

OBJECTIVES: The clinical characteristics, risk factors and survival prognosis of pericardial effusion (PE) after haematopoietic stem cell transplantation (HSCT) in children were investigated. METHODS: Clinical data of children who underwent HSCT at the Children's Hospital Affiliated with Chongqing Medical University from January 2016 to December 2022 were analysed retrospectively. Cox proportional hazards regression and the Kaplan-Meier method were used to analyse the risk factors for post-HSCT PE and its impact on outcomes, respectively. RESULTS: We enrolled 452 patients with HSCT: 307 males and 145 females, with a median age of 3.4 (1.8 to 6.5) years at transplantation. Forty-five patients (10%) had PE within a median time of 25 (10.5 to 44) days, 42 (93%) within 100 days. Three patients with large PE were treated with pericardiocentesis and drainage, while the others were treated conservatively. Of the 45 patients with PE, 24 survived, and their PE disappeared after treatment. Graft-versus-host disease (GVHD) grade, abnormal pre-HSCT electrocardiogram, hepatic veno-occlusive disease (HVOD), pulmonary infection and Epstein-Barr virus (EBV) infection were risk factors for PE. The overall survival (OS) rates at 1, 3, and 5 years were 86.0%, 84.2%, and 82.3%, respectively. PE had a significant negative effect on OS after HSCT (P < 0.0001). Particularly, one patient with large PE died of pericardial tamponade. CONCLUSIONS: Post-HSCT PE usually occurred within 100 days. GVHD grade, abnormal pre-HSCT electrocardiogram, HVOD, pulmonary infection and EBV infection were closely related to PE. PE had a significant negative effect on OS rate.

Higher abatacept exposure after transplant decreases acute GVHD risk without increasing adverse events.

In the ABA2 study, the T-cell costimulation blockade agent, abatacept, was safe and effective in preventing acute graft-versus-host disease (aGVHD) after unrelated-donor hematopoietic cell transplant (HCT), leading to US Food and Drug Administration approval. Here, we performed a determination of abatacept pharmacokinetics (PK), which enabled an examination of how abatacept exposure-response relationships affected clinical outcomes. We performed a population PK analysis of IV abatacept using nonlinear mixed-effect modeling and assessed the association between abatacept exposure and key transplant outcomes. We tested the association between the trough after dose 1 (Ctrough_1) and grade (GR) 2 or 4 aGVHD (GR2-4 aGVHD) through day +100. An optimal Ctrough_1 threshold was identified via recursive partitioning and classification tree analysis. This demonstrated that abatacept PK was characterized by a 2-compartment model with first-order elimination. The ABA2 dosing regimen was based on previous work targeting a steady-state abatacept trough of 10 µg/mL. However, a higher Ctrough_1 (≥39 µg/mL, attained in ∼60% of patients on ABA2) was associated with a favorable GR2-4 aGVHD risk (hazard ratio, 0.35; 95% confidence interval, 0.19-0.65; P < .001), with a Ctrough_1 <39 µg/mL associated with GR2-4 aGVHD risk indistinguishable from placebo (P = .37). Importantly, no significant association was found between Ctrough_1 and key safety indicators, including relapse, and cytomegalovirus or Epstein-Barr virus viremia. These data demonstrate that a higher abatacept Ctrough_1 (≥39 µg/mL) was associated with a favorable GR2-4 aGVHD risk, without any observed exposure-toxicity relationships. This trial was registered at www.clinicaltrials.gov as #NCT01743131.

Haematopoietic stem cell transplantation for hepatitis-associated aplastic anaemia and non-hepatitis-associated aplastic anaemia: A propensity score-matched analysis.

To validate the efficacy and safety of haematopoietic stem cell transplantation (HSCT) in hepatitis-associated aplastic anaemia (HAAA) patients, we reviewed 260 patients who underwent HSCT for acquired aplastic anaemia and eventually included 30 HAAA patients and 90 non-HAAA patients using propensity score matching. In the HAAA group, the estimated 5-year overall survival rate (75.8% vs. 86.5%, p = 0.409), failure-free survival (FFS) rate (74.0% vs. 83.2%, p = 0.485), graft-versus-host disease (GVHD)-free FFS rate (61.2% vs. 67.6%, p = 0.669) after HSCT were slightly lower but not statistically significant than those in the non-HAAA group. Both groups did not significantly differ in engraftment, post-transplant severe infection, cytomegalovirus (CMV) or Epstein-Barr virus viraemia, or GVHD incidences. The patterns of immune reconstitution were broadly consistent between the two groups. When stratifying HAAA patients according to donor type, no significant differences in survival, transplant-related mortality, or GVHD cumulative incidences were observed. CMV viraemia (68.7% vs 8.3%, p = 0.009) occurred more commonly in haploidentical donor (HID) transplants than in matched sibling donor transplants. However, early CMV disease incidence (5.6% vs. 0.0%, p = 1.000) was low. Overall, the post-transplant outcomes of HAAA patients were comparable to those of non-HAAA patients after balancing potential confounders, and HID-HSCT can offer an alternative curative option for HAAA.

Screening costs associated with donor selection for fecal microbiota transplantation for treatment of PD-1 refractory melanoma patients.

The gut microbiome acts as a tumor-extrinsic regulator of responses to immune-checkpoint inhibitors (ICIs) targeting PD-1 and CTLA-4 receptors. Primary resistance to anti-PD-1 ICI can be reversed via responder-derived fecal microbiota transplant (FMT) in patients with refractory melanoma. Efforts to create stool banks for FMT have proved difficult. Therefore, we aimed to establish a novel donor-screening program to generate responder-derived FMT for use in PD-1 refractory melanoma. Candidate PD-1 responder donors and PD-1 refractory recipients were recruited via clinic-based encounters at the University of Pittsburgh Medical Center hospitals. Eligible donors and recipients underwent physician assessment and screening of serum, stool and nasopharynx for transmissible agents, which included SARS-CoV-2 modification. The cost of donor and recipient screening was calculated. Initially, 29 donors were screened with 14 eligible donors identified after exclusion; of the 14 donors, eight were utilized in clinical trials. The overall efficiency of screening was 48%. Seroprevalence rates for cytomegalovirus, Epstein-Barr virus, HSV-2, HHV-6, HTLV-1, HTLV-2, and syphilis were similar to published statistics from healthy blood donors in the USA. Donor stool studies indicated a 3.6% incidence of E. histolytica and norovirus, 3.7% incidence of giardia and 7.1% incidence of C. difficile. A single donor tested positive for SARS-CoV-2 in stool only. The cost for finding a single eligible donor was $2260.24 (pre-COVID) and $2,460.24 (post-COVID). The observed screening efficiency suggests that a well-resourced screening program can generate sufficient responder-derived donor material for clinical trial purposes. Eliminating testing for low-prevalence organisms may improve cost-effectiveness.

Late airway complications following pediatric liver transplantation: A case series.

BACKGROUND: Late airway complications, as consequence of immunosuppression following pediatric liver transplantation are uncommonly reported. METHODS: In this retrospective case series, we describe two young children presenting with symptoms of airway obstruction, secondary to differing pathologies in the supraglottic airway, as a result of immunosuppression following liver transplantation. RESULTS: Case 1, a 2-year-old girl who presented with stridor 12-months following liver transplantation, was found to have a proliferative soft tissue mass involving the supraglottic larynx. Biopsies were consistent with infiltrative eosinophilic laryngitis and associated eosinophilic esophagitis. Case 2, a 12-month-old female who presented with stridor 5-months following liver transplantation, was found to have an exophytic soft tissue mass involving the supraglottis and hypopharynx. Biopsies revealed polymorphic Epstein-Barr virus (EBV) driven post-transplant lymphoproliferative disease (PTLD). Case 1 was managed with local resection and high dose oral corticosteroids. Case 2 responded to debulking of the necrotic supraglottic mass, reduction of immunosuppression and rituximab. CONCLUSION: A high index of suspicion needs to be maintained for complications of immunosuppression for appropriate diagnosis of airway presentations following pediatric liver transplantation. Further research is necessary to improve early detection and consolidate management strategies for these airway lesions.

Hypogammaglobulinemia in Children After Hematopoietic Stem Cell Transplantation and Rituximab Treatment: Relevance of B Cell Subsets.

Rituximab (RTX) is widely employed to treat Epstein-Barr virus reactivation in children undergoing Hematopoietic Cell Transplantation (HCT). The resulting loss of B cells may cause persistent hypogammaglobulinemia. This retrospective cross-sectional study aims to identify flow cytometry biomarkers associated with persistent hypogammaglobulinemia in patients receiving RTX after HCT. We analyzed 5 patients (cases group) requiring immunoglobulin substitution due to low level of IgG (IgG <5 g/L) detected after RTX treatment and 5 patients (controls group) not requiring long-term immunoglobulin (Ig) substitution. We investigated the B cell reconstitution, and in patients group we observed a significantly lower count in B total, IgD+CD27+ marginal B cells and IgD-CD27+ switched-memory B cells, after a median of 5 years from HCT, compared with the control group. Despite the importance limits of our study and the heterogeneity of our data (age of included patients, time of evaluation, interval between RTX dose and assessment) we conclude that RTX given early after HCT might cause a deranged B cell maturation, contributing to the delation in B cell recovery following HCT, and switched memory and marginal zone B cell counts could be a promising biomarker to identify patients requiring long-term Ig substitution.

Immune cell function assay and T lymphocyte counts lack association with rejection or infection in pediatric heart transplant recipients.

INTRODUCTION: Immune cell function assay (ICFA) and CD3 lymphocyte counts have been considered to be useful in discerning the overall intensity of immunosuppression in pediatric orthotopic heart transplant (OHT) recipients. METHODS: The aim of this retrospective analysis was to evaluate trends of ICFA and CD3 lymphocyte counts and their association with adverse outcomes post-OHT. RESULTS: A total of 381 ICFA and 493 CD3 laboratory values obtained in 78 patients within six months post-OHT were analyzed. There were 14 patients treated for biopsy-proven acute rejection, four of whom had ISHLT grade 2R/3A rejection. In patients with rejection versus those without, CD3 and ICFA values were 122 (IQR 74.5-308) cells/mm2 and 224.5 (IQR 132-343.5) ng/ml compared to 231.8 (IQR 68-421) cells/m2 and 191 (IQR 81.5-333) ng/mL (p = NS for both). Twenty-six patients had at least one detectable cytomegalovirus or Epstein-Barr virus DNAemia within the study timeframe. In patients with viremia versus those without, CD3 and ICFA values were 278.5 (IQR 68-552) cells/mm2 and 130 (IQR 48-284) ng/ml compared to 195 (IQR 74.5-402.5) cells/mm2 and 212 (IQR 89-342) ng/ml (p = NS for both). CONCLUSIONS: No association was found between these immune markers and adverse outcomes. In the absence of larger pediatric studies justifying the role of these tests in identifying elevated risk profiles post OHT, we do not recommend their routine use.

Risk factors and outcome of concurrent and sequential multiviral cytomegalovirus, Epstein-Barr virus, BK virus, adenovirus and other viral reactivations in transplantation.

PURPOSE OF REVIEW: Reactivation of viral infections occurs frequently in immunosuppressed populations, particularly in solid organ (SOT) or allogeneic haematopoietic cell (HCT) transplant patients. Concurrent and sequential multivirus infections are common, yet risk factors and outcomes remain unclear. This review aims to identify the patients vulnerable to multivirus infections and characterize the impact of increased viral burden to formulate prevention and treatment strategies. RECENT FINDINGS: Incidences of up to 89% in SOT and 36% in HCT have been reported for two viruses, and 32% in SOT and 28% in HCT for at least three viruses. Risk factors appear related to an increased burden of immunosuppression, with most viral coinfections occurring within 12 months of transplantation. Direct viral complications such as cytomegalovirus disease are more frequent in coinfected patients, with documented prolonged duration of viraemia, higher viral load and increased end-organ disease. Graft dysfunction, acute rejection and graft-vs.-host disease (GVHD) have also been associated. Increased mortality is reported in the HCT population. SUMMARY: Multivirus infections occur in a significant proportion of transplant patients and is linked to immunosuppressive burden. There is increasing evidence that this leads to worse graft and patient outcomes. Further prospective studies are required to further comprehensively characterise viral epidemiology, mechanisms and treatment strategies to ameliorate this risk.

Third-party CMV- and EBV-specific T-cells for first viral reactivation after allogeneic stem cell transplant.

Virus-specific T-cells (VSTs) from third-party donors mediate short- and long-term antiviral effects in allogeneic hematopoietic stem cell transplant (HSCT) recipients with relapsed or refractory viral infections. We investigated early administration of third-party VSTs, together with antiviral therapy in patients requiring treatment for first cytomegalovirus (CMV) or Epstein-Barr virus (EBV) infection. Thirty HSCT patients were treated with 1 to 4 VST infusions (2 × 107 cells/m2; CMV n=27, EBV n=3) at a median of 4 days after initiation of antiviral treatment. The overall viral response rate was 100%, with a complete response (CR) rate of 94%. Of the 28 patients who achieved a CR, 23 remained virus PCR negative (n=9) or below quantitation limit (n=14) for the duration of follow-up. Four patients had brief episodes of quantifiable reactivation not requiring additional therapy, and one required a second infusion after initial CR, remaining PCR negative thereafter. All 3 patients treated for EBV post-transplant lymphoproliferative disorder achieved sustained CR. Rates of aGVHD and cGVHD after infusion were 13% and 23%, respectively. There were no serious infusion-related adverse events. VST infusion was associated with rapid recovery of CD8+CD45RA-CD62L- and a slower recovery of CD4+CD45RA-CD62L- effector memory T-cells; CMV-specific T-cells comprised up to 13% of CD8+ cells. At 1 year post-transplant, non-relapse mortality was 10%, cumulative incidence of relapse was 7%, overall survival was 88% and 25 of 27 patients had ECOG status of 0 or 1. Early administration of third-party VSTs in conjunction with antiviral treatment appears safe and leads to excellent viral control and clinical outcomes. Registered on Australian New Zealand Clinical Trials Registry as #ACTRN12618000343202.