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1.
Letermovir for Cytomegalovirus infection in pediatric patients undergoing allogenic hematopoietic stem cell transplantation: a real-life study by the Infectious Diseases Working Group of Italian Association of Pediatric Hematology-Oncology (AIEOP)
Galaverna, F., Baccelli, F., Zama, D., Tridello, G., Masetti, R., Soncini, E., Mura, R., Barzaghi, F., Colombini, A., Prunotto, G., et al
Bone marrow transplantation. 2024
Abstract
Letermovir prophylaxis revolutionized the approach to Cytomegalovirus infection in adult hematopoietic stem cell transplant (HCT), while data in pediatric setting are still lacking. We retrospectively analyzed 87 HCT children transplanted in 11 AIEOP centers receiving letermovir as off-label indication between January 2020 and November 2022. Letermovir was used as primary, secondary prophylaxis or CMV treatment in 39, 26 and 22 cases, respectively; no discontinuation due to toxicity was reported. Median duration was 100 days (14-256) for primary and 96 days (8-271) for secondary prophylaxis, respectively. None of the patients experienced CMV-clinically significant reactivation during Letermovir primary prophylaxis; one patient developed breakthrough infection during secondary prophylaxis, and 10 and 1 patient experienced asymptomatic CMV-reactivation and CMV-primary infection after drug discontinuation, respectively. Median duration of letermovir in CMV treatment was 40 days (7-134), with 4/22 patients suffering CMV-pneumonia, with an overall response rate of 86.4%. With a median follow-up of 10.7 months (8.2-11.8), estimated 1-year overall survival was 86%; no CMV-related deaths were reported in prophylaxis groups. This is the largest report on Letermovir use in pediatric HCT; real-life data confirm an excellent toxicity profile, with high efficacy as CMV prophylaxis; results in CMV-infection treatment should be investigated in larger, prospective trials.
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2.
Influence of invasive aspergillosis during acute leukaemia treatment on survival after allogeneic stem cell transplantation: a prospective study of the EBMT Infectious Diseases Working Party
Penack, O., Tridello, G., Salmenniemi, U., Martino, R., Khanna, N., Perruccio, K., Fagioli, F., Richert-Przygonska, M., Labussière-Wallet, H., Maertens, J., et al
EClinicalMedicine. 2024;67:102393
Abstract
BACKGROUND Infections are the main reason for mortality during acute leukaemia treatment and invasive aspergillosis (IA) is a major concern. Allogeneic stem cell transplantation (alloSCT) is a standard therapy and often is the only live-saving procedure in leukaemia patients. The profound immunodeficiency occurring after alloSCT led to high IA-associated mortality in the past. Therefore, patients with IA were historically considered transplant-ineligible. Recently, there has been improvement of anti-fungal management including novel anti-fungal agents. As a result, more leukaemia patients with IA are undergoing alloSCT. Outcome has not been prospectively assessed. METHODS We performed a prospective study in acute leukaemia patients undergoing alloSCT to analyse the impact of a prior history of probable or proven IA (pre-SCT IA). The primary endpoint was 1-year non-relapse mortality (NRM). Relapse free survival and overall survival were analysed as secondary endpoints. FINDINGS 1439 patients were included between 2016 and 2021. The incidence of probable or proven pre-SCT IA was 6.0% (n = 87). The cumulative incidence of 1-year NRM was 17.3% (95% CI 10.2-26.0) and 11.2% (9.6-13.0) for patients with and without pre-SCT IA. In multivariate analyses the hazard ratio (HR) for 1-year NRM was 2.1 (1.2-3.6; p = 0.009) for patients with pre-SCT IA. One-year relapse-free survival was inferior in patients with pre-SCT IA (59.4% [48.3-68.9] vs. 70.4 [67.9-72.8]; multivariate HR 1.5 [1.1-2.1]; p = 0.02). Consequently, 1-year overall survival was lower in patients with pre-SCT IA (68.8% [57.8-77.4] vs. 79.0% [76.7-81.1]; multivariate HR 1.7 [1.1-2.5]; p = 0.01). INTERPRETATION Pre-SCT IA remains to be significantly associated with impaired alloSCT outcome. On the other hand, more than two thirds of patients with pre-SCT IA were alive at one year after alloSCT. IA is not anymore an absolute contraindication for alloSCT because the majority of patients with IA who undergo alloSCT benefit from this procedure. FUNDING There was no external funding source for this study.
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3.
Open-Label Randomized Controlled Study of Ciprofloxacin vs Rifaximin as Neutropenia Prophylaxis in Allogeneic Hematopoietic Stem Cell Transplantation
Gavriilaki, E., Mallouri, D., Laspa, E., Papakonstantinou, A., Lazaridou, A., Varelas, C., Baldoumi, E., Giannakopoulou, A., Demosthenous, C., Vardi, A., et al
Transplantation proceedings. 2024
Abstract
Loss of microbiota diversity has been clearly associated with poor outcomes in the allogeneic hematopoietic stem cell transplantation setting. However, the choice of the optimal antibiotic prophylaxis during the pre-engraftment phase remains unclear. We designed a prospective randomized study to compare our standard-of-care neutropenia prophylaxis (ciprofloxacin) with rifaximin. We enrolled 38 consecutive adult patients who underwent allogeneic hematopoietic stem cell transplantation setting and were randomly assigned to receive ciprofloxacin (20 patients) or rifaximin (18 patients) at day -1. Pretransplant and transplant characteristics did not differ between groups. Cumulative incidence (CI) of acute graft-vs-host disease grade II to IV and moderate/severe chronic graft-vs-host disease was similar in both groups. With a median follow-up of 13.2 months (range, 6.8-30.2) in surviving patients, the 1-year CI of relapse was 20.8% in ciprofloxacin vs 17.8% in rifaximin (P = .616). Importantly, the 1-year CI of treatment-related mortality was significantly reduced in the ciprofloxacin group (10.2% vs 27.8%, P = .032), leading to higher 1-year overall survival (88.9% vs 74.6%, P = .038). In Cox-regression multivariate analysis, antibiotic prophylaxis remained the only predictor of overall survival, independently of donor type, disease risk index, and moderate/severe chronic graft-vs-host disease. Further studies are needed to assess the effects on microbiota diversity and confirm these outcomes.
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4.
Disparities in CMV infection rates by race and ethnicity among pediatric allogeneic hematopoietic cell transplant recipients at a single center
Boge, C. L. K., McDonough, M. H., Newman, A. M., Blumenstock, J., Elgarten, C. W., Freedman, J. L., Olson, T. S., Li, Y., Fisher, B. T.
Transplantation and cellular therapy. 2024
Abstract
BACKGROUND Previous literature has reported cytomegalovirus (CMV) infection rate disparities between race and ethnicity groups of hematopoietic cell transplant (HCT) recipients. Because race and ethnicity categorizations are social constructs unlikely to affect biological systems, it is likely there are covariates on the pathway to CMV detection, known as mediators, which would explain the observed disparity. Recent developments in mediation analysis methods enable the analysis of time-to-event outcomes, allowing an investigation of these disparities to also consider the timing of infection detection relative to HCT. OBJECTIVE This study aimed to explore whether racial and ethnic CMV infection disparities existed within a population of HCT recipients at our center and whether clinical covariates explained any observed association. STUDY DESIGN The study includes all allogeneic HCTs performed at the Children's Hospital of Philadelphia January 2004-April 2017 where subjects were CMV polymerase chain reaction (PCR) negative pre-transplant, had known donor/recipient CMV serology, and under blood PCR CMV surveillance. Subjects were followed for 100 days post-HCT. Accelerated failure time models using subject's reported race/ethnicity, dichotomized into non-Hispanic White (NHW) and not NHW, as exposure and time to CMV detection as outcome examined whether selected clinical factors (donor/recipient CMV serostatus, recipient age, transplant indication, hematopoietic cell source, match quality) mediated any identified exposure-outcome association. RESULTS The analysis included 348 HCT episodes from 335 subjects; 86 episodes (24.7%) detected CMV via PCR testing. The accelerated failure time model without mediators estimated non-NHW subjects had fewer CMV-free survival days (Time Ratio: 0.21, 95% Confidence Interval: 0.10-0.44). Any hypothesized mediator mediated at most 5% of the total association between race/ethnicity and time to CMV detection. CONCLUSION Non-NHW HCT recipients had fewer CMV-free survival days than NHW recipients; none of the clinical factors hypothesized to mediate this association accounted for a significant component of total association. Further research should focus on non-clinical factors influenced by systemic racism to better understand its effect on CMV infection among HCT recipients.
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5.
A phase II randomized, placebo-controlled, multicenter trial to evaluate the efficacy of cytomegalovirus PepVax vaccine in preventing cytomegalovirus reactivation and disease after allogeneic hematopoietic stem cell transplant
Nakamura, R., La Rosa, C., Yang, D., Hill, J. A., Rashidi, A., Choe, H., Zhou, Q., Lingaraju, C. R., Kaltcheva, T., Longmate, J., et al
Haematologica. 2024
Abstract
Not available.
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6.
HHV-6B detection and host gene expression implicate HHV-6B as pulmonary pathogen after hematopoietic cell transplant
Hill, J. A., Lee, Y. J., Vande Vusse, L. K., Xie, H., Chung, E. L., Waghmare, A., Cheng, G. S., Zhu, H., Huang, M. L., Hill, G. R., et al
Nature communications. 2024;15(1):542
Abstract
Limited understanding of the immunopathogenesis of human herpesvirus 6B (HHV-6B) has prevented its acceptance as a pulmonary pathogen after hematopoietic cell transplant (HCT). In this prospective multicenter study of patients undergoing bronchoalveolar lavage (BAL) for pneumonia after allogeneic HCT, we test blood and BAL fluid (BALF) for HHV-6B DNA and mRNA transcripts associated with lytic infection and perform RNA-seq on paired blood. Among 116 participants, HHV-6B DNA is detected in 37% of BALs, 49% of which also have HHV-6B mRNA detection. We establish HHV-6B DNA viral load thresholds in BALF that are highly predictive of HHV-6B mRNA detection and associated with increased risk for overall mortality and death from respiratory failure. Participants with HHV-6B DNA in BALF exhibit distinct host gene expression signatures, notable for enriched interferon signaling pathways in participants clinically diagnosed with idiopathic pneumonia. These data implicate HHV-6B as a pulmonary pathogen after allogeneic HCT.
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7.
Adoptive therapy with cytomegalovirus-specific cytotoxic T lymphocytes for refractory cytomegalovirus DNAemia and disease after allogeneic haematopoietic stem cell transplantation
Jiang, Z., Fan, Z., Zhang, T., Lin, R., Xu, H., Xu, N., Huang, F., Chi, P., Ou, X., Wang, Z., et al
British journal of haematology. 2024
Abstract
Cytomegalovirus (CMV) DNAemia and disease are common complications in patients undergoing allogeneic haematopoietic stem cell transplantation (allo-HSCT). Few studies have compared the efficacy and safety of the HSCT donor and third-party CMV-specific cytotoxic T lymphocytes (CMV-CTLs) in the treatment of CMV DNAemia and disease. In this study, we retrospectively compared the efficacy and safety of HSCT donor and third-party CMV-CTLs in patients with refractory CMV DNAemia or disease after allo-HSCT at our centre from January 2017 to September 2021. Fifty-three patients who received CMV-CTL therapy were enrolled, including 40 in the donor group and 13 in the third-party group, and they were adults aged 18 years or older. Within 6 weeks of treatment, 26 (65.0%) and 9 (69.2%) patients achieved complete response in the donor and third-party groups (p = 1.000). The 2-year overall survival was 59.6% (95% CI 46.1%-77.1%) and 53.8% (32.6%-89.1%) in the donor and third-party groups (p = 0.860). Four (10.0%) patients in the donor group and two (15.4%) patients in the third-party group developed acute graft-versus-host disease within 3 months after CMV-CTL infusions. In conclusion, our data suggest that donor and third-party CMV-CTLs have comparable efficacy and safety for refractory CMV DNAemia and disease.
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8.
Clinical characteristics and outcomes of allogeneic hematopoietic stem cell transplantation recipients with coronavirus disease 2019 caused by the Omicron variant: a prospective, observational cohort study
Fan, S., Mo, X., Zhang, X., Xu, L., Wang, Y., Yan, C., Chen, H., Zhang, Y., Cheng, Y., Sun, Y., et al
Annals of hematology. 2024
Abstract
We aimed to describe the clinical characteristics, particularly the occurrence and risk factors of severe/critical illness, in allogeneic hematopoietic stem cell (allo-HSCT) recipients infected with coronavirus disease 2019 (COVID-19) caused by Omicron variant in an observational prospective study (n = 311). The median time from allo-HSCT to COVID-19 diagnosis was 8.5 months (range 0.8-106.1) months. Four patients (1.3%) were reported to be asymptomatic during Omicron variant infection, and 135 (43.4%) patients showed lower respiratory tract disease. Thirty-four (10.9%) patients were categorized into serious infection (severe illness n = 25; critical illness n = 9) and the median duration from COVID-19 diagnosis to serious infections was 6 days (range, 0-29) days. Thirteen (4.2%) and 6 (1.9%) patients required intensive care unit care and invasive mechanical ventilation, respectively. Receiving more than 1 type of immunosuppressive therapies at COVID-19 diagnosis was associated with severity and persistence of infection. Six patients (1.9%) died after diagnosis of COVID-19 infection. The 4-week probability of overall survival after COVID-19 diagnosis was 98.7%, which was 100% and 88.2% for non-serious and serious infection group (P < 0.001), respectively. Thus, we observed a relatively low serious infection and mortality rate in allo-HSCT recipients infected with COVID-19 caused by Omicron variant.
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9.
Monitoring of adenoviremia in pediatric patients undergoing hematopoietic stem cell transplantation: Is it alone sufficient to predict adenoviral disease?
Kanık Yüksek, S., Arman Bilir, Ö, Erat, T., Gülhan, B., Kanbur Ş, M., Bayhan, Gİ, Ok Bozkaya, İ, Özkaya Parlakay, A., Özbek, N. Y.
Pediatric transplantation. 2024;28(1):e14696
Abstract
BACKGROUND We aimed to evaluate our pediatric HSCT recipients routinely monitored for adenoviremia and to determine the adequacy of this monitoring in predicting adenoviral disease (AD). METHODS A retrospective cohort of patients who underwent allogeneic HSCT between January 2021 and August 2022, and routinely monitored for adenoviremia by real-time PCR was included in our survey. Demographic and clinical data of the patients were recorded. Incidence rates, risk factors, and mortality rates related to adenoviremia, and AD were analyzed. RESULTS Among 104 HSCTs performed in 94 patients adenovirus (AdV) was revealed in 27 (26%) episodes and adenoviremia in 18 (17.3%) HSCT episodes. AD without adenoviremia developed in nine episodes (8.6%). Disseminated disease was significantly more frequently detected in episodes with adenoviremia (p = .008). GVHD was independent risk factor for AdV detection (OR: 8.6, 95% CI: 2.03-33.7, p = .001). Viremia developed within a shorter time interval after HSCT in isolated episodes of adenoviremia compared to those with concomitant AD (p = .006). Initial and peak viral loads were significantly higher in adenoviremia with AD (p < .001). Mortality was higher in the AdV-detected episodes (p < .001) than in the AdV-undetected episodes. AdV-related mortality was found to be 22.2%. Adenoviremia increased the risk of mortality (OR: 1.2, 95% CI: 0.22-1.33, p = .01). CONCLUSIONS Adenoviremia monitoring is an important process in the detection of AD. Since some patients may develop AD without accompanying by adenoviremia, monitoring for AdV in blood samples should be supported with other monitoring methods in order to evaluate the probable involvement of different organs or systems.
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10.
Cmv reactivations in allogeneic hematopoietic stem cell transplant from hla-matched and haploidentical donors with post-transplant cyclophosphamide
Chorão, P., Henriques, M., Villalba, M., Montoro, J., Balaguer-Roselló, A., González, E. M., Gómez, M. D., Gómez, I., Solves, P., Santiago, M., et al
Transplantation and cellular therapy. 2024
Abstract
BACKGROUND Cytomegalovirus (CMV) reactivations cause significant morbidity in allogeneic hematopoietic stem cell transplant (HSCT) recipients. Graft-versus-host disease prophylaxis (GVHD) with post-transplant cyclophosphamide (PTCy) is associated with an increased risk of CMV infections, with limited data on HSCT with PTCy assessing together matched sibling donors (MSD), matched unrelated donors (MUD), and haploidentical donors (HAPLO). OBJECTIVES Characterize CMV reactivation and recurrences, in patients with hematologic malignancies undergoing HSCT from MSD, MUD, and HAPLO using PTCy as GVHD prophylaxis in the pre-letermovir era. Analyze risk factors of CMV reactivations, including GVHD as a time-dependent variable, on the incidence and mortality associated with CMV infections. STUDY DESIGN We analyzed CMV reactivations in patients undergoing HSCT from 160 MSD, 124 MUD and 82 HAPLO from a single institution. Uniform GVHD prophylaxis with PTCy, sirolimus and mycophenolate mofetil was given, irrespective of donor type. RESULTS Overall, 46% of patients had at least one CMV reactivation. The 1-year cumulative incidence of CMV infection was 39% for MSD, 44% for MUD, and 62% for HAPLO donors (p<0.001), with 96% of reactivations occurring before day +100. Multivariate analysis identified factors associated with the first CMV reactivation, including HAPLO donor, positive recipient CMV serology, older patient age, and grade II-IV acute GVHD. The 1-year cumulative incidence of second reactivation from HSCT was 13%. Recipient CMV seropositivity, older patient age and grade II-IV acute GVHD remained the adverse factors for second CMV reactivation in multivariate analysis, but not type of donor. The 1-year cumulative incidence of third reactivation from HSCT was 4.4%. Ten cases of CMV disease were recorded, with no attributable deaths. Nevertheless, the hazard for NRM was superior for patients who had a CMV reactivation in multivariate time-dependent Cox-model analysis. CONCLUSIONS CMV reactivation is frequent in HSCT with PTCy among patients not receiving letermovir prophylaxis. Identified risk factors include the use of HAPLO donor, recipient CMV seropositivity, and acute grade II-IV GVHD. The prevalence of recurrent CMV reactivations pose a noteworthy issue, especially after acute GVHD, warranting trials for secondary prophylaxis strategies.