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1.
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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Favorable outcomes of hematopoietic stem cell transplantation in children and adolescents with Diamond-Blackfan anemia
Strahm, B., Loewecke, F., Niemeyer, C. M., Albert, M., Ansari, M., Bader, P., Bertrand, Y., Burkhardt, B., Da Costa, L. M., Ferster, A., et al
Blood advances. 2020;4(8):1760-1769
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Abstract
Diamond-Blackfan anemia (DBA) is a congenital pure red cell aplasia associated with congenital abnormalities and cancer predisposition. Allogeneic hematopoietic stem cell transplantation (HSCT) can correct the hematological phenotype and is indicated in transfusion-dependent patients. In 70 children reported to the German DBA and French HSCT registries, HSCT was performed from 1985 to 2017. Median age at HSCT was 5.5 years (range, 0.9-17.3 years). Two-thirds of patients (64%) were transplanted from a matched sibling donor (MSD), and most procedures were performed after the year 1999 (73%). Primary engraftment was achieved in all patients. One patient developed secondary graft failure. Cumulative incidence of acute graft-versus-host disease (GVHD) was 24% for degrees II-IV (95% confidence interval [CI], 16% to 37%) and 7% for degrees III-IV (95% CI, 3% to 17%); cumulative incidence of chronic GVHD was 11% (95% CI, 5% to 22%). The probability of chronic GVHD-free survival (cGFS) was 87% (95% CI, 79% to 95%) and significantly improved over time (<2000: 68% [95% CI, 47% to 89%] vs ≥2000: 94% [95% CI, 87% to 100%], P < .01). cGFS was comparable following HSCT from a MSD and an unrelated donor (UD). Of note, no severe chronic GVHD or deaths were reported following MSD-HSCT after 1999. The difference of cGFS in children transplanted <10 years of age compared with older patients did not reach statistical significance (<10 years: 90% [95% CI, 81% to 99%] vs 10-18 years 78% [95% CI, 58% to 98%]). In summary, these data indicate that HSCT is efficient and safe in young DBA patients and should be considered if a MSD or matched UD is available. HSCT for transfusion dependency only must be critically discussed in older patients.
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Haematopoietic Cell Transplantation in Chronic Granulomatous Disease: a Study on 712 Children and Adults
Chiesa, R., Wang, J., Blok, H. J., Hazelaar, S., Neven, B., Moshous, D., Schulz, A. S., Hoenig, M., Hauck, F., Al Seraihy, A., et al
Blood. 2020
Abstract
Chronic Granulomatous Disease (CGD) is a primary immunodeficiency resulting in life-threatening infections and inflammatory complications. Allogeneic hematopoietic cell transplantation (allo-HCT) can cure patients, but indication to transplant remains controversial. We performed a retrospective multicentre study on 712 patients with CGD undergoing allo-HCT transplanted in EBMT centres between 1993 and 2018. We studied 635 children (aged < 18 years) and 77 adults. Median follow-up was 45 months. Median age at transplant was 7 years (range: 0.1-48.6). Kaplan-Meier estimates of OS and EFS at 3 years were 85.7% (95% CI, 82.8-88.5) and 75.8% (95% CI, 72.3-79.3), respectively. On MVA, older age was associated with reduced survival (HR= 1.69, p= 0.0001) and increased chronic GVHD (HR 1.35, p=0.01). Nevertheless OS and EFS at 3 years for patients ≥ 18 years was 76% (95%CI, 66-86) and 69% (95%CI, 57-80), respectively. Use of one antigen-mismatched donors was associated with reduced OS (HR= 2.29, p= 0.01) and EFS (HR 2.37, p=0.001). No significant difference was found in OS, but a significantly reduced EFS (HR 3.69 p=0.001), in the small group who received a transplant from a donor with more than one antigen-mismatch. Choice of conditioning regimen did not influence OS or EFS. In conclusion we report an excellent outcome after allo-HCT in CGD, with low incidence of graft failure and mortality in all ages. Older patients and recipients of one antigen-mismatched grafts have a less favourable outcome. Transplant should be strongly considered at a younger age and particularly in the presence of a well-matched donor.
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Supportive care during pediatric hematopoietic stem cell transplantation: beyond infectious diseases. A report from workshops on supportive care of the Pediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT)
Nava, T., Ansari, M., Dalle, J. H., de Heredia, C. D., Gungor, T., Trigoso, E., Falkenberg, U., Bertaina, A., Gibson, B., Jarisch, A., et al
Bone marrow transplantation. 2020
Abstract
Hematopoietic stem cell transplantation (HSCT) is currently the standard of care for many malignant and nonmalignant blood diseases. As several treatment-emerging acute toxicities are expected, optimal supportive measurements critically affect HSCT outcomes. The paucity of good clinical studies in supportive practices gives rise to the establishment of heterogeneous guidelines across the different centers, which hampers direct clinical comparison in multicentric studies. Aiming to harmonize the supportive care provided during the pediatric HSCT in Europe, the Pediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT) promoted dedicated workshops during the years 2017 and 2018. The present paper describes the resulting consensus on the management of sinusoidal obstructive syndrome, mucositis, enteral and parenteral nutrition, iron overload, and emesis during HSCT.
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Presence of centromeric but absence of telomeric group B KIR haplotypes in stem cell donors improve leukaemia control after HSCT for childhood ALL
Babor, F., Peters, C., Manser, A. R., Glogova, E., Sauer, M., Potschger, U., Ahlmann, M., Cario, G., Feuchtinger, T., Gruhn, B., et al
Bone marrow transplantation. 2019
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.
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Low incidence of symptomatic osteonecrosis after allogeneic HSCT in children with high-risk or relapsed ALL - results of the ALL-SCT 2003 trial
Kuhlen, M., Bader, P., Sauer, M., Albert, M. H., Gruhn, B., Gungor, T., Kropshofer, G., Lang, P., Lawitschka, A., Metzler, M., et al
British journal of haematology. 2018
Abstract
Osteonecrosis (ON) was prospectively assessed in 557 children and adolescents in the Berlin-Frankfurt-Munster Stem Cell Transplantation in children with acute lymphoblastic leukaemia 2003 trial. Median age at haematopoietic stem cell transplantation (HSCT) was 10.3 years (range 0.5-26). Cumulative incidence of symptomatic ON (sON) was 9% at 5 years (standard deviation 1%), median time from HSCT to diagnosis of sON was 12.4 months (range 1-126). Multivariate analysis identified age at HSCT [10-15 years vs. <10 years: hazard ratio (HR) 3.73, P = 0.009; >15 years vs. <10 years: HR 5.46, P = 0.001], diagnosis of sON prior to HSCT and chronic graft-versus-host disease (yes versus no: HR 2.696, P = 0.015) as significant independent risk factors for the development of sON.
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Risk assessment of relapse by lineage-specific monitoring of chimerism in children undergoing allogeneic stem cell transplantation for acute lymphoblastic leukemia
Preuner, S., Peters, C., Potschger, U., Daxberger, H., Fritsch, G., Geyeregger, R., Schrauder, A., von Stackelberg, A., Schrappe, M., Bader, P., et al
Haematologica. 2016;101(6):741-6
Abstract
UNLABELLED Allogeneic hematopoietic stem cell transplantation is required as rescue therapy in about 20% of pediatric patients with acute lymphoblastic leukemia. However, the relapse rates are considerable, and relapse confers a poor outcome. Early assessment of the risk of relapse is therefore of paramount importance for the development of appropriate measures. We used the EuroChimerism approach to investigate the potential impact of lineage-specific chimerism testing for relapse-risk analysis in 162 pediatric patients with acute lymphoblastic leukemia after allogeneic stem cell transplantation in a multicenter study based on standardized transplantation protocols. Within a median observation time of 4.5 years, relapses have occurred in 41/162 patients at a median of 0.6 years after transplantation (range, 0.13-5.7 years). Prospective screening at defined consecutive time points revealed that reappearance of recipient-derived cells within the CD34(+) and CD8(+) cell subsets display the most significant association with the occurrence of relapses with hazard ratios of 5.2 (P=0.003) and 2.8 (P=0.008), respectively. The appearance of recipient cells after a period of pure donor chimerism in the CD34(+) and CD8(+) leukocyte subsets revealed dynamics indicative of a significantly elevated risk of relapse or imminent disease recurrence. Assessment of chimerism within these lineages can therefore provide complementary information for further diagnostic and, potentially, therapeutic purposes aiming at the prevention of overt relapse. This study was registered at clinical. TRIALS gov with the number NC01423747.
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Association of busulfan exposure with survival and toxicity after haemopoietic cell transplantation in children and young adults: a multicentre, retrospective cohort analysis
Bartelink, I. H., Lalmohamed, A., van Reij, E. M., Dvorak, C. C., Savic, R. M., Zwaveling, J., Bredius, R. G., Egberts, A. C., Bierings, M., Kletzel, M., et al
The Lancet Haematology. 2016;3(11):e526-e536
Abstract
BACKGROUND Intravenous busulfan combined with therapeutic drug monitoring to guide dosing improves outcomes after allogeneic haemopoietic cell transplantation (HCT). The best method to estimate busulfan exposure and optimum exposure in children or young adults remains unclear. We therefore assessed three approaches to estimate intravenous busulfan exposure (expressed as cumulative area under the curve [AUC]) and associated busulfan AUC with clinical outcomes in children or young adults undergoing allogeneic HCT. METHODS In this retrospective analysis, patients from 15 centres in the Netherlands, USA, Canada, Switzerland, UK, Italy, Germany, and Australia who received a busulfan-based conditioning regimen between March 18, 2001, and Feb 12, 2015, were included. Cumulative AUC was calculated by numerical integration using non-linear mixed effect modelling (AUCNONMEM), non-compartmental analysis (AUC from 0 to infinity [AUC0-] and to the next dose [AUC0-tau]), and by individual centres using various approaches (AUCcentre). The main outcome of interest was event-free survival. Other outcomes of interest were graft failure or relapse, or both; transplantation-related mortality; acute toxicity (veno-occlusive disease or acute graft versus-host disease [GvHD]); chronic GvHD; overall survival; and chronic-GvHD-free event-free survival. We used propensity-score-adjusted Cox proportional hazard models, Weibull models, and Fine-Gray competing risk regressions for statistical analyses. FINDINGS 790 patients were enrolled, 674 of whom were included: 274 (41%) with malignant and 400 (59%) with non-malignant disease. Median age was 4.5 years (IQR 1.4-10.7). The median busulfan AUCNONMEM was 74.4 mg x h/L (95% CI 31.1-104.6), which correlated with the standardised method AUC0- (r2=0.74), but the latter correlated poorly with AUCcentre (r2=0.35). Estimated 2-year event-free survival was 69.7% (95% CI 66.2-73.0). Event-free survival at 2 years was 77.0% (95% CI 72.1-82.9) in the 257 patients with an optimum intravenous busulfan AUC of 78-101 mg x h/L compared with 66.1% (60.9-71.4) in the 235 patients at the low historical target of 58-86 mg x h/L and 49.5% (29.2-66.0) in the 44 patients with a high (>101 mg x h/L) busulfan AUC (p=0.011). Compared with the low AUC group, graft failure or relapse occurred less frequently in the optimum AUC group (hazard ratio [HR] 0.57, 95% CI 0.39-0.84; p=0.0041). Acute toxicity (HR 1.69, 1.12-2.57; p=0.013) and transplantation-related mortality (2.99, 1.82-4.92; p<0.0001) were significantly higher in the high AUC group (>101 mg x h/L) than in the low AUC group (<78 mg x h/L), independent of indication; no difference was noted between AUC groups for chronic GvHD (<78 mg x h/L vs >=78 mg x h/L, HR 1.30, 95% CI 0.73-2.33; p=0.37). INTERPRETATION Improved clinical outcomes are likely to be achieved by targeting the busulfan AUC to 78-101 mg x h/L using a new validated pharmacokinetic model for all indications. FUNDING Research Allocation Program and the UCSF Helen Friller Family Comprehensive Cancer Center and the Mt Zion Health Fund of the University of California, San Francisco.Copyright © 2016 Elsevier Ltd. All rights reserved.