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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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Second allogeneic stem cell transplantation can rescue a significant proportion of patients with JMML relapsing after first allograft
Vinci, L., Flotho, C., Noellke, P., Lebrecht, D., Masetti, R., de Haas, V., De Moerloose, B., Dworzak, M., Hasle, H., Güngör, T., et al
Bone marrow transplantation. 2023
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Risk factors for a severe disease course in children with SARS-COV-2 infection following hematopoietic cell transplantation in the pre-Omicron period: a prospective multinational Infectious Disease Working Party from the European Society for Blood and Marrow Transplantation group (EBMT) and the Spanish Group of Hematopoietic Stem Cell Transplantation (GETH) study
Averbuch, D., de la Camara, R., Tridello, G., Knelange, N. S., Bykova, T. A., Ifversen, M., Dobsinska, V., Ayas, M., Hamidieh, A. A., Pichler, H., et al
Bone marrow transplantation. 2023;:1-9
Abstract
Risk factors for severe SARS-Cov-2 infection course are poorly described in children following hematopoietic cell transplantation (HCT). In this international study, we analyzed factors associated with a severe course (intensive care unit (ICU) admission and/or mortality) in post-HCT children. Eighty-nine children (58% male; median age 9 years (min-max 1-18)) who received an allogeneic (85; 96%) or an autologous (4; 4%) HCT were reported from 28 centers (18 countries). Median time from HCT to SARS-Cov-2 infection was 7 months (min-max 0-181). The most common clinical manifestations included fever (37; 42%) and cough (26; 29%); 37 (42%) were asymptomatic. Nine (10%) children following allo-HCT required ICU care. Seven children (8%) following allo-HCT, died at a median of 22 days after SARS-Cov-2 diagnosis. In a univariate analysis, the probability of a severe disease course was higher in allo-HCT children with chronic GVHD, non-malignant disease, immune suppressive treatment (specifically, mycophenolate), moderate immunodeficiency score, low Lansky score, fever, cough, coinfection, pulmonary radiological findings, and high C-reactive protein. In conclusion, SARS-Cov-2 infection in children following HCT was frequently asymptomatic. Despite this, 10% needed ICU admission and 8% died in our cohort. Certain HCT, underlying disease, and SARS-Cov-2 related factors were associated with a severe disease course.
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Low rate of nonrelapse mortality in under 4-year-olds with ALL given chemo-conditioning for HSCT: Phase III FORUM study
Bader, P., Poetschger, U., Dalle, J. H., Moser, L. M., Balduzzi, A. C., Ansari, M., Buechner, J., Güngör, T., Ifversen, M., Kriván, G., et al
Blood advances. 2023
Abstract
Allogeneic hematopoietic stem cell transplantation (HSCT) is highly effective for treating pediatric high-risk or relapsed acute lymphoblastic leukemia (ALL). In young children, total body irradiation (TBI) is associated with severe late sequelae. In the FORUM study (NCT01949129), we assessed safety, event-free survival (EFS), and overall survival (OS) of two TBI-free conditioning regimens in children with ALL <4 years old. Patients received fludarabine (Flu), thiotepa (Thio), and either busulfan (Bu) or treosulfan (Treo) before HSCT. From 2013 to 2021, 191 children were transplanted and observed for ≥6 months (median follow-up: 3 years). 3-year OS was 0.63 (95% confidence interval [95% CI]: 0.52-0.72) and 0.76 (95% CI: 0.64-0.84) for Flu/Thio/Bu and Flu/Thio/Treo (p = 0.075), respectively. 3-year EFS was 0.52 (95% CI: 0.41-0.61) and 0.51 (95% CI: 0.39-0.62), respectively (p = 0.794). Cumulative incidence of non-relapse mortality (NRM) and relapse at 3 years were 0.06 (95% CI: 0.02-0.12) versus 0.03 (95% CI: <0.01-0.09) (p = 0.406) and 0.42 (95% CI: 0.31-0.52) versus 0.45 (95% CI: 0.34-0.56) (p = 0.920), respectively. Grade >1 acute graft-versus-host disease (GvHD) occurred in 29% of patients receiving Flu/Thio/Bu and 17% receiving Flu/Thio/Treo (p = 0.049), while grade 3-4 occurred in 10% and 9% (p = 0.813). 3-year incidence of chronic GvHD was 0.07 (95% CI: 0.03-0.13) versus 0.05 (95% CI: 0.02-0.11), respectively (p = 0.518). In conclusion, both chemo-conditioning regimens were well tolerated and NRM was low. However, relapse was the major cause of treatment failure.
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Improved outcomes over time and higher mortality in CMV seropositive allogeneic stem cell transplantation patients with COVID-19; An infectious disease working party study from the European Society for Blood and Marrow Transplantation registry
Ljungman, P., Tridello, G., Piñana, J. L., Ciceri, F., Sengeloev, H., Kulagin, A., Mielke, S., Yegin, Z. A., Collin, M., Einardottir, S., et al
Frontiers in immunology. 2023;14:1125824
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Editor's Choice
Abstract
INTRODUCTION COVID-19 has been associated with high morbidity and mortality in allogeneic hematopoietic stem cell transplant (allo-HCT) recipients. METHODS This study reports on 986 patients reported to the EBMT registry during the first 29 months of the pandemic. RESULTS The median age was 50.3 years (min - max; 1.0 - 80.7). The median time from most recent HCT to diagnosis of COVID-19 was 20 months (min - max; 0.0 - 383.9). The median time was 19.3 (0.0 - 287.6) months during 2020, 21.2 (0.1 - 324.5) months during 2021, and 19.7 (0.1 - 383.9) months during 2022 (p = NS). 145/986 (14.7%) patients died; 124 (12.6%) due to COVID-19 and 21 of other causes. Only 2/204 (1%) fully vaccinated patients died from COVID-19. There was a successive improvement in overall survival over time. In multivariate analysis, increasing age (p<.0001), worse performance status (p<.0001), contracting COVID-19 within the first 30 days (p<.0001) or 30 - 100 days after HCT (p=.003), ongoing immunosuppression (p=.004), pre-existing lung disease (p=.003), and recipient CMV seropositivity (p=.004) had negative impact on overall survival while patients contracting COVID-19 in 2020 (p<.0001) or 2021 (p=.027) had worse overall survival than patients with COVID-19 diagnosed in 2022. DISCUSSION Although the outcome of COVID-19 has improved, patients having risk factors were still at risk for severe COVID-19 including death.
PICO Summary
Population
Adults and children who tested PCR positive to COVID-19 after previous allogeneic transplant, and were reported to the EBMT registry (n=986)
Intervention
Analysis of the outcome of COVID-19 during important phases of the COVID-19.
Comparison
Patients contracting COVID-19 at different time points of the pandemic were compared
Outcome
The median age was 50.3 years (min - max; 1.0 - 80.7). The median time from most recent HCT to diagnosis of COVID-19 was 20 months (min - max; 0.0 - 383.9). The median time was 19.3 (0.0 - 287.6) months during 2020, 21.2 (0.1 - 324.5) months during 2021, and 19.7 (0.1 - 383.9) months during 2022 (p = NS). 145/986 (14.7%) patients died; 124 (12.6%) due to COVID-19 and 21 of other causes. Only 2/204 (1%) fully vaccinated patients died from COVID-19. There was a successive improvement in overall survival over time. In multivariate analysis, increasing age, worse performance status, contracting COVID-19 within the first 30 days or 30 - 100 days after HCT, ongoing immunosuppression, pre-existing lung disease, and recipient CMV seropositivity had negative impact on overall survival while patients contracting COVID-19 in 2020 or 2021 had worse overall survival than patients with COVID-19 diagnosed in 2022.
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Hematopoietic stem cell transplantation in children and adolescents with GATA2-related myelodysplastic syndrome
Bortnick, R., Wlodarski, M., de Haas, V., De Moerloose, B., Dworzak, M., Hasle, H., Masetti, R., Starý, J., Turkiewicz, D., Ussowicz, M., et al
Bone marrow transplantation. 2021
Abstract
GATA2 deficiency is a heterogeneous multi-system disorder characterized by a high risk of developing myelodysplastic syndrome (MDS) and myeloid leukemia. We analyzed the outcome of 65 patients reported to the registry of the European Working Group (EWOG) of MDS in childhood carrying a germline GATA2 mutation (GATA2(mut)) who had undergone hematopoietic stem cell transplantation (HSCT). At 5 years the probability of overall survival and disease-free survival (DFS) was 75% and 70%, respectively. Non-relapse mortality and relapse equally contributed to treatment failure. There was no evidence of increased incidence of graft-versus-host-disease or excessive rates of infections or organ toxicities. Advanced disease and monosomy 7 (-7) were associated with worse outcome. Patients with refractory cytopenia of childhood (RCC) and normal karyotype showed an excellent outcome (DFS 90%) compared to RCC and -7 (DFS 67%). Comparing outcome of GATA2(mut) with GATA2(wt) patients, there was no difference in DFS in patients with RCC and normal karyotype. The same was true for patients with -7 across morphological subtypes. We demonstrate that HSCT outcome is independent of GATA2 germline mutations in pediatric MDS suggesting the application of standard MDS algorithms and protocols. Our data support considering HSCT early in the course of GATA2 deficiency in young individuals.
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Hematopoietic cell transplantation in severe combined immunodeficiency: the SCETIDE 2006-2014 European cohort
Lankester, A. C., Neven, B., Mahlaoui, N., von Asmuth, E. G., Courteille, V., Alligon, M., Albert, M. H., Serra, I. B., Bader, P., Balashov, D., et al
The Journal of allergy and clinical immunology. 2021
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Editor's Choice
Abstract
BACKGROUND Hematopoietic stem cell transplantation (HSCT) represents a curative treatment for patients with severe combined immunodeficiency (SCID), a group of monogenic immune disorders with an otherwise fatal outcome. OBJECTIVE To perform a comprehensive multicenter analysis of genotype-specific HSCT outcome including detailed analysis of immune reconstitution (IR) and the predictive value for clinical outcome. METHODS HSCT outcome was studied in 338 patients with genetically confirmed SCID, transplanted in 2006-2014 and registered in the SCETIDE registry. In a representative subgroup of n=152 patients data on IR and long-term clinical outcome were analyzed. RESULTS 2-years OS was similar with matched family and unrelated donors and superior to mismatched donor HSCT (p < 0.001). The 2-year EFS was similar in matched and mismatched unrelated donor and less favorable in mismatched related donor (MMRD) HSCT (p < 0.001). Genetic subgroups did not differ in 2-year OS (p=0.1) and EFS (p=0.073). In multivariate analysis, pretransplant infections and use of MMRD were associated with less favorable OS and EFS. With a median follow-up of 6.2 years [range 2.0-11.8 years], 73/152 IR cohort patients were alive and well without immunoglobulin dependency. IL2R?-JAK3-IL7R deficient SCID, myeloablative conditioning, matched donor HSCT, and naïve CD4 T lymphocytes > 0.5x10e3/µL at +1-year were identified as independent predictors of favorable clinical and immunological outcome. CONCLUSION Recent advances in HSCT in SCID patients have resulted in improved OS and EFS in all genotypes and donor types. To achieve a favorable long term outcome, treatment strategies should aim for optimal naïve CD4 T lymphocyte regeneration.
PICO Summary
Population
Patients with severe combined immunodeficiency (SCID) transplanted in the years 2006-2014 and reported to the SCETIDE registry (n=338) Long-term outcomes were assessed in a representative subgroup (n=152)
Intervention
Assessment of the impact of donor source and SCID genetic diagnosis on transplant outcomes
Comparison
None
Outcome
2-years OS was similar with matched family and unrelated donors and superior to mismatched donor HSCT. The 2-year EFS was similar in matched and mismatched unrelated donor and less favorable in mismatched related donor (MMRD) HSCT. Genetic subgroups did not differ in 2-year OS and EFS. In multivariate analysis, pretransplant infections and use of MMRD were associated with less favorable OS and EFS. With a median follow-up of 6.2 years [range 2.0-11.8 years], 73/152 IR cohort patients were alive and well without immunoglobulin dependency IL-2 receptor gamma chain/Janus kinase 3/IL-7 receptor–deficient SCID, myeloablative conditioning, matched donor HSCT, and naïve CD4 T lymphocytes > 0.5x10e3/µL at +1-year were identified as independent predictors of favorable clinical and immunological outcome.
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Myeloablative conditioning for allo-HSCT in pediatric ALL: FTBI or chemotherapy?-A multicenter EBMT-PDWP study
Willasch, A. M., Peters, C., Sedlacek, P., Dalle, J. H., Kitra-Roussou, V., Yesilipek, A., Wachowiak, J., Lankester, A., Prete, A., Hamidieh, A. A., et al
Bone marrow transplantation. 2020
Abstract
Although most children with acute lymphoblastic leukemia (ALL) receive fractionated total body irradiation (FTBI) as myeloablative conditioning (MAC) for allogeneic hematopoietic stem cell transplantation (allo-HSCT), it is an important matter of debate if chemotherapy can effectively replace FTBI. To compare outcomes after FTBI versus chemotherapy-based conditioning (CC), we performed a retrospective EBMT registry study. Children aged 2-18 years after MAC for first allo-HSCT of bone marrow (BM) or peripheral blood stem cells (PBSC) from matched-related (MRD) or unrelated donors (UD) in first (CR1) or second remission (CR2) between 2000 and 2012 were included. Propensity score weighting was used to control pretreatment imbalances of the observed variables. 3.054 patients were analyzed. CR1 (1.498): median follow-up (FU) after FTBI (1.285) and CC (213) was 6.8 and 6.1 years. Survivals were not significantly different. CR2 (1.556): median FU after FTBI (1.345) and CC (211) was 6.2 years. Outcomes after FTBI were superior as compared with CC with regard to overall survival (OS), leukemia-free survival (LFS), relapse incidence (RI), and nonrelapse mortality (NRM). However, we must emphasize the preliminary character of the results of this retrospective "real-world-practice" study. These findings will be prospectively assessed in the ALL SCTped 2012 FORUM trial.
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Total Body Irradiation or Chemotherapy Conditioning in Childhood ALL: A Multinational, Randomized, Noninferiority Phase III Study
Peters, C., Dalle, J. H., Locatelli, F., Poetschger, U., Sedlacek, P., Buechner, J., Shaw, P. J., Staciuk, R., Ifversen, M., Pichler, H., et al
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2020;:Jco2002529
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Editor's Choice
Abstract
PURPOSE Total body irradiation (TBI) before allogeneic hematopoietic stem cell transplantation (HSCT) in pediatric patients with acute lymphoblastic leukemia (ALL) is efficacious, but long-term side effects are concerning. We investigated whether preparative combination chemotherapy could replace TBI in such patients. PATIENTS AND METHODS FORUM is a randomized, controlled, open-label, international, multicenter, phase III, noninferiority study. Patients = 18 years at diagnosis, 4-21 years at HSCT, in complete remission pre-HSCT, and with an HLA-compatible related or unrelated donor were randomly assigned to myeloablative conditioning with fractionated 12 Gy TBI and etoposide versus fludarabine, thiotepa, and either busulfan or treosulfan. The noninferiority margin was 8%. With 1,000 patients randomly assigned in 5 years, 2-year minimum follow-up, and one-sided alpha of 5%, 80% power was calculated. A futility stopping rule would halt random assignment if chemoconditioning was significantly inferior to TBI (EudraCT: 2012-003032-22; ClinicalTrials.gov: NCT01949129). RESULTS Between April 2013 and December 2018, 543 patients were screened, 417 were randomly assigned, 212 received TBI, and 201 received chemoconditioning. The stopping rule was applied on March 31, 2019. The median follow-up was 2.1 years. In the intention-to-treat population, 2-year overall survival (OS) was significantly higher following TBI (0.91; 95% CI, 0.86 to 0.95; P < .0001) versus chemoconditioning (0.75; 95% CI, 0.67 to 0.81). Two-year cumulative incidence of relapse and treatment-related mortality were 0.12 (95% CI, 0.08 to 0.17; P < .0001) and 0.02 (95% CI, < 0.01 to 0.05; P = .0269) following TBI and 0.33 (95% CI, 0.25 to 0.40) and 0.09 (95% CI, 0.05 to 0.14) following chemoconditioning, respectively. CONCLUSION Improved OS and lower relapse risk were observed following TBI plus etoposide compared with chemoconditioning. We therefore recommend TBI plus etoposide for patients > 4 years old with high-risk ALL undergoing allogeneic HSCT.
Clinical Commentary
Dr. Julia Wolf, University Hospitals Bristol and Weston NHS Foundation Trust
What is known?
Allogeneic haematopoietic stem cell transplantation (HSCT) provides a potential curative treatment option for paediatric patients with high risk acute lymphoblastic leukaemia (ALL). Pre-transplant conditioning regimes with total body irradiation (TBI) have resulted in encouraging overall and relapse-free survival but may cause serious long-term side effects. As a result, several studies have investigated TBI-free regimes. A large meta-analysis (1) which included seven randomised controlled trials comparing TBI-based with chemoconditioning regimes demonstrated significantly lower treatment related mortality (TRM) but no overall survival (OS) advantage with TBI-based regimes. A further small randomised study (2) found significantly higher event-free survival (EFS) with TBI-based regimes in patients with unrelated donors, but a non-significant difference only in patients with matched sibling donors. Concerns about late effects of TBI on growth, cognitive function and secondary malignancy however remain. A single centre retrospective study (3) in paediatric ALL concluded that triosulphan based regimes were safe and efficacious while a similar review (4) in adult patients suggested that busulphan and clofarabine could provide an alternative to TBI. This paper reports on the FORUM study. It compares TBI with chemoconditioning regimes to investigate whether optimal chemoconditioning regimens could replace TBI in paediatric patients with high-risk ALL.
What did this paper set out to examine?
This is the largest randomised, controlled, open-label, international, multicentre, phase III trial comparing TBI plus etoposide with chemoconditioning (fludarabine, thiotepa and busulfan or triosulfan) in paediatric ALL to date. It investigates whether chemoconditioning is non-inferior to TBI-based regimes with the primary endpoint of OS. It is also the first study to directly and prospectively compare these regimes in terms of disease-free survival and short- and long-term adverse events. The study aimed to recruit 1000 patients.
What did they show?
Improved OS and lower relapse risk were observed following TBI plus etoposide compared with chemoconditioning. Patients ≤18 years old at diagnosis and aged 4-21 at HSCT with high risk ALL in complete morphological remission with HLA compatible related or unrelated donor were included in the study. Patients were randomised 1:1 to 12Gy TBI with etoposide versus fludarabine, thiotepa and busulfan or triosulphan conditioning. Patients were well matched for baseline characteristics and demographics. Randomisation was stopped early due significant inferiority of chemoconditioning compared with TBI-based regime.
Results
Following randomisation of 417 patients, a futility stopping rule was applied because patients receiving chemoconditioning with fludarabine, thiotepa, and busulfan or treosulfan had inferior OS to those receiving TBI plus etoposide. Two-year OS was 0.91 (95% CI, P <.0001) following TBI versus 0.75 (95% CI) following chemoconditioning. Median follow up was 2.1 years. Relapse was the commonest reason for treatment failure and out of 67 patients who relapsed, there was no difference in OS between conditioning regimes. There was no difference in serious adverse events or GvHD rates between the groups.
What are the implications for practice and for future work?
While TBI is associated with potentially serious long-term side effects, this study supports growing evidence demonstrating improved outcomes for patients undergoing TBI-based conditioning. Here patients receiving TBI-based conditioning had a significantly lower risk of relapse and TRM than those given chemoconditioning.
Of note, TRM in this trial was low compared to previously reported studies. FOCUS reported a 2-year OS and EFS rate of 0.91 and 0.91 respectively, which is the lowest documented TRM in HSCT for high-risk paediatric ALL to date. Additionally, other risk factors thought to impact on outcomes (e.g. leukaemia phenotype, MRD pre-transplant, donor type, etc) were not found to be significant in FOCUS. Only remission status (CR1 vs CR2) and conditioning regime influenced OS and EFS. This may be in part explained by the strong attempts within this study to reduce MRD prior to HSCT in all patients.
This was a noninferiority study which required a sample size of 1000 patients with 2-year minimum follow-up to make analysis of primary outcomes feasible. As the majority of relapses in paediatric ALL occur in the first 24 months, it is unlikely that longer follow up would result in dramatic changes to outcomes.
Non-randomised recruitment in FORUM to assess long-term side effects of TBI, such as secondary malignancy, in FORUM is ongoing. However, no difference in adverse events or incidence of GvHD was found between study groups. The study reports a composite end point of 2-year GVHD-free, relapse-free survival of 72% (95% CI) following TBI plus etoposide and 51% (95% CI, p= .0003) following chemoconditioning which might be a benchmark for future investigations.
PICO Summary
Population
Patients diagnosed with acute lymphoblastic leukaemia at or before 18 years of age, who underwent HSCT aged 4-21 years (n=413)
Intervention
TBI conditioning (n=212)
Comparison
Chemoconditioning: fludarabine, thiotepa, and either busulfan or treosulfan (n=201)
Outcome
The median follow-up was 2.1 years. In the intention-to-treat population, 2-year overall survival (OS) was significantly higher following TBI (0.91) versus chemoconditioning (0.75). Two-year cumulative incidence of relapse and treatment-related mortality were 0.12 and 0.02 following TBI and 0.33 and 0.09 following chemoconditioning, respectively.
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Diagnostic Parameters of Adenoviremia in Pediatric Stem Cell Transplant Recipients
Kosulin, K., Pichler, H., Lawitschka, A., Geyeregger, R., Lion, T.
Frontiers in microbiology. 2019;10:414
Abstract
Despite recent progress in the diagnostic risk assessment of human adenovirus (HAdV) infections in immunocompromised patients, clinical complications mediated by these viruses continue contributing to significant morbidity and mortality, particularly in the pediatric hematopoietic allogeneic stem cell transplant (HSCT) setting. Current data highlight the importance of monitoring stool samples to assess the risk of invasive HAdV infections in children undergoing HSCT. The advent of novel, more effective antiviral treatment options might permit successful virus control even at the stage of systemic infection, thus increasing the interest in optimized HAdV monitoring in peripheral blood (PB). We have screened over 300 pediatric HCST recipients by serial monitoring of stool and PB specimens, and identified 31 cases of invasive HAdV infection by quantitative pan-adenovirus RQ-PCR analysis of consecutive PB specimens. The diagnostic parameters assessed included HAdV peak levels (PL) and the time-averaged area under the curve (AAUC) of virus copy numbers. The predictive value for patient outcome reflected by non-relapse and HAdV-related mortality was determined. The patients were assigned to quartiles based on their PL and AAUC, and the readouts were highly correlated (p < 0.0001). Non-relapse mortality in patients by AAUC quartile (lowest to highest) was 26, 50, 75, and 86%, respectively, and AAUC was strongly correlated with non-relapse mortality (p < 0.0001), while the association between PL and non-relapse mortality was less pronounced (p = 0.013). HAdV-related mortality was absent or very low in patients within the two lower quartiles of both PL and AAUC, and increased to ≥70% in the upper two quartiles. Despite the significant correlation of PL and AAUC with patient outcome, it is necessary to consider that the risk of non-relapse mortality even within the lowest quartile was still relatively high, and it might be difficult therefore to translate the results into differential treatment approaches. By contrast, the correlation with HAdV-related mortality might permit the identification of a low-risk patient subset. Nevertheless, the well-established correlation of HAdV shedding into the stool and intestinal expansion of the virus with the risk of invasive infection will expectedly remain an essential diagnostic parameter in the pediatric HSCT setting.