Abstract

BACKGROUND Currently, no estimates can be made on the impact of hematopoietic stem cell transplantation on allergy transfer or cure of the disease. By using component-resolved diagnosis we prospectively investigated fifty donor-recipient pairs undergoing allogeneic stem cell transplantation. This allowed calculating the rate of transfer or maintenance of allergen-specific responses in the context of stem cell transplantation. METHODS Allergen-specific IgE and IgG to 156 allergens was measured pre-transplantation in 50 donors and recipients and at six, 12 and 24 months in recipients post-transplantation by allergen microarray. Based on a mixed effects model, we determined risks of transfer of allergen-specific IgE or IgG responses 24 months post-transplantation. RESULTS After undergoing stem cell transplantation, 94% of allergen-specific IgE responses were lost. Two years post-transplantation, recipients' allergen-specific IgE was significantly linked to the pre-transplantation donor or recipient status. The estimated risk to transfer and maintain individual IgE responses to allergens by stem cell transplantation was 1.7% and 2.3% respectively. Allergen-specific IgG, which served as a surrogate marker of maintaining protective IgG responses, was highly associated with the donor's (31.6%) or the recipient's (28%) pre-transplantation response. CONCLUSION Hematopoietic stem cell transplantation profoundly reduces allergen-specific IgE responses but also comes with a considerable risk to transfer allergen-specific immune responses. These findings facilitate clinical decision making regarding allergic diseases in the context of hematopoietic stem cell transplantation. In addition, it provides prospective data to estimate the risk of transmitting allergen-specific responses via hematopoietic stem cell transplantation.

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.

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.

Abstract

Severe infections (SI) significantly impact on non-relapse mortality after hematopoietic stem cell transplantation (HSCT). We assessed 432 children and adolescents with acute lymphoblastic leukemia (ALL) after total body irradiation based myeloablative HSCT within the multicenter ALL-BFM-SCT 2003 trial for SI grade 3 or higher according to common terminology criteria for adverse events. A total 172 patients experienced at least one SI. Transplantation from matched unrelated donors (MUD) was associated with any type of SI in the pre-engraftment period (hazard ratio [HR]: 2.57; P < 0.001) and with any SI between day +30 and + 100 (HR: 2.91; P = 0.011). Bacterial (HR: 2.24; P = 0.041) and fungal infections (HR: 4.06; P = 0.057) occurred more often in the pre-engraftment phase and viral infections more often before day +30 (HR: 2.66; P = 0.007) or between day +30 and + 100 (HR: 3.89; P = 0.002) after HSCT from MUD as compared to matched sibling donors. Chronic GvHD was an independent risk factor for any type of SI after day +100 (HR: 2.57; P < 0.002). We conclude that allogeneic HSCT from MUD in children and adolescents with pediatric ALL is associated with higher infection rates, which seems attributable to an intensified GvHD prophylaxis including serotherapy and methotrexate.

Abstract

Although allogeneic hematopoietic stem-cell transplantation (HSCT) provides high cure rates for children with high-risk acute lymphoblastic leukaemia (ALL), relapses remain the main cause of treatment failure. Whereas donor killer cell immunoglobulin-like receptor (KIR) genotype was shown to impact on relapse incidence in adult myeloid leukaemia similar studies in paediatric ALL are largely missing. Effect of donor KIR genotype on transplant outcome was evaluated in 317 children receiving a first myeloablative HSCT from an HLA-matched unrelated donor or sibling within the prospective ALL-SCT-BFM-2003 trial. Analysis of donor KIR gene polymorphism revealed that centromeric presence and telomeric absence of KIR B haplotypes was associated with reduced relapse risk. A centromeric/telomeric KIR score (ct-KIR score) integrating these observations correlated with relapse risk (hazard ratio (HR) 0.58; P = 0.002) while it had no impact on graft-versus-host disease or non-relapse mortality. In multivariable analyses ct-KIR score was associated with reduced relapse risk (HR 0.58; P = 0.003) and a trend towards improved event-free survival (HR 0.76; P = 0.059). This effect proved independent of MRD level prior to HSCT. Our data suggest that in children with ALL undergoing HSCT after myeloablative conditioning, donor selection based on KIR genotyping holds promise to improve clinical outcome by decreasing relapse risk and prolonged event-free survival.

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.

Abstract

Torque Teno virus (TTV) in humans is characterized by ubiquitous occurrence in peripheral blood (PB), without any related disease described to date. Several studies reported a significant increase of TTV plasma DNA levels in allogeneic transplant recipients, and suggested a correlation of elevated virus titers with immunosuppression and transplant-related complications. However, the site of viral replication in this setting has remained unclear. We have studied TTV in serial plasma specimens derived from 43 pediatric allogeneic hematopoietic stem cell transplantation (HSCT) recipients by RQ-PCR, and found increasing TTV-DNA levels in all patients post-transplant, with a peak around day +100 and maximum virus copy numbers reaching 4 x 10E9/ml. To assess whether the virus replicates in PB-cells, leukocyte subsets including granulocytes, monocytes, NK-cells, T- and B-lymphocytes were serially isolated by flow-sorting for TTV analysis in 19 patients. The virus was undetectable in most cell types, but was identified in granulocytes in all instances, revealing a median DNA copy number increase of 1.8 logs between days +30-100 post-transplant. Our data therefore provide evidence for TTV replication in granulocytes in this setting. In a control cohort of immunocompetent children and in HSCT recipients before day +30, TTV positivity in granulocytes was less common (33%), and the copy numbers were considerably lower. However, rising TTV replication about 2 weeks after granulocyte engraftment (>500 cells/mul) was observed suggesting that granulocyte recovery might be required for TTV expansion in severely immunosuppressed transplant recipients.

Abstract

Veno-occlusive disease (VOD) remains a serious complication after allogeneic hematopoietic stem cell transplantation (HSCT). Prophylactic use of defibrotide (DF) might further reduce VOD rates but has no impact on the incidence of severe VOD or VOD-associated mortality. We investigated the cost-effectiveness of prophylactic DF according to the British Committee for Standards in Haematology/British Society for Blood and Marrow Transplantation guidelines in 348 children who underwent transplantation between 2001 and 2014 in our hospital, 138 of whom were at risk for VOD. The VOD incidence was 7.4% for the total cohort. Patients at risk had a higher incidence of VOD compared with patients without risk factors (15.2% versus 2.4%, P<.0001). VOD occurred more often in patients after busulfan-based myeloablative conditioning than in patients after total body irradiation (11.2% versus 3.5%, P=.001). Donor types or the transplantation-related mortality (TRM) risk score did not correlate with VOD incidence. In 81% of patients who responded to therapeutic DF, VOD resolved completely. Overall VOD-associated mortality was .3% for the complete cohort, 3.7% for patients diagnosed with VOD, and 20% for patients with severe VOD. Neither the cumulative incidence of TRM (19%+/-8% versus 17%+/-2%, P=.706) nor the median length of hospitalization differed between patients with VOD and patients without. The median costs per HSCT in patients with VOD were about one-third higher than the overall median costs per transplantation at our institution. The calculated total costs of prophylactic DF treatment for 138 patients at risk was almost 6 times as high as the incremental costs for patients with VOD. We conclude that prophylactic DF for children at risk for VOD is not cost-effective with respect to TRM and length of hospital stay. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Abstract

The impact of persistent mixed chimerism (MC) after haematopoietic stem cell transplantation (HSCT) remains unclarified. We investigated the incidence of MC in peripheral blood beyond day +50 after HSCT and its impact on rejection, chronic graft-versus-host disease (c-GvHD) and relapse in 161 children receiving allogeneic HSCT for haematological malignancies. The 1-year incidence of late MC was 26%. Spontaneous conversion to complete donor chimerism (CC) occurred in 43% of patients as compared to 62% after donor lymphocyte infusions. No graft rejection occurred. The 1-year incidence of c-GvHD was 20 +/- 7% for MC, and 18 +/- 4% for CC patients (P = 0.734). The 3-year cumulative incidence of relapse (CIR) according to chimerism status at days +50 and +100 was 22 +/- 4% for CC patients vs. 22 +/- 8% for MC patients (day +50; P = 0.935) and 21 +/- 4% vs. 20 +/- 7% (day +100; P = 0.907). Three-year CIRs in patients with persistent MC and patients with CC/limited MC were comparable (8 +/- 7% vs. 19 +/- 4%; P = 0.960). HSCT for acute leukaemia or myelodysplastic syndrome as secondary malignancies (hazard ratio (HR) 4.7; P = 0.008), for AML (HR 3.0; P = 0.02) and from mismatched donors (HR 3.1; P = 0.03) were independent factors associated with relapse. Our data suggest that late MC neither protects from c-GvHD nor does it reliably predict impending disease relapse. Copyright © 2016 John Wiley & Sons Ltd.

Abstract

Flow cytometric routine CD34 analysis enumerates hematopoietic stem and progenitor cells irrespective of their subpopulations although this might predict engraftment dynamics and immune reconstitution. We established a multi-color CD34 assay containing CD133, CD45RA, CD10, CD38 and CD33. We examined PBSC, donor bone marrow (BMd) and BM of patients 1 year after allografting (BM1y) regarding their CD34 subset composition, which differed significantly amongst those materials: the early CD45RA(-)CD133(+)CD38(low) subpopulations were significantly more frequent in PBSC than in BMd, and very low in BM1y. Vice versa, clearly more committed CD34 stages prevailed in BM, particularly in BM1y where the proportion of multi-lymphoid and CD38(++) B-lymphoid precursors was highest (mean 59%). CD33 was expressed at different intensity on CD45RA(+/-)CD133(+/-) subsets allowing discrimination of earlier from more committed myeloid precursors. Compared with conventional CD34(+) cell enumeration, the presented multi-color phenotyping is a qualitative approach defining different CD34 subtypes in any CD34 source. Its potential impact to predict engraftment kinetics and immune reconstitution has to be evaluated in future studies.