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2.
Stem Cells Dev ; 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33446053

RESUMO

Steroid-refractory graft-versus-host disease (GvHD) is a life-threatening complication after allogeneic hematopoietic stem cell transplantation (alloHSCT). Alternative treatment options are often insufficient. Several studies have proven the efficacy of mesenchymal stromal cells (MSC) in the treatment of therapy-refractory acute GvHD in adult and pediatric patients. Long-term data in pediatric patients is scarce. In this retrospective analysis, a total of 25 patients with a median age of 10.6 years (range 0.6-22.1 years) who received bone marrow-derived MSC after alloHSCT for the treatment of steroid-refractory °III and °IV GvHD, were analyzed. The median observation period of the surviving patients was 9.3 years (1.3-12.7 years) after HSCT. Among the 25 patients, 10 (40.0%) died (relapse (n=3), multi-organ failure (n=6), cardiorespiratory failure (n=1)) at median 0.5 years (0.2-2.3 years) after HSCT. Partial response and complete remission (PR, CR) of the GvHD was achieved in 76.0% and 24.0% of the patients, respectively. Transplant-related mortality was 0% in the patients who achieved CR after MSC treatment, and 26.3% for those with PR. A median improvement by one intestinal or liver GvHD stage (range 1-4) could be achieved after MSC application. No potentially MSC-related long-term adverse effects, e. g. secondary malignancy, were identified. In conclusion, the intravenous application of allogeneic MSC was safe and proved effective for the treatment of steroid-refractory GvHD. However, larger, prospective and randomized trials are needed to evaluate these findings.

3.
Artigo em Inglês | MEDLINE | ID: mdl-33338535

RESUMO

BACKGROUND: PSTPIP1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome is a novel genetic disorder, causing hypercalprotectinemia and hyperzincemia with inflammatory complications accompanied by cytopenia. Immunosuppressive and/or anti-cytokine therapy is of limited effect. OBJECTIVES: Due to cytokine production in non-hematopoietic tissues, the potential therapeutic effect of allogeneic hematopoietic stem cell transplantation (HSCT) in autoinflammatory disorders, including PAMI syndrome, has remained uncertain. METHODS: Five patients with PAMI syndrome underwent allogeneic HSCT with myeloablative (4) or reduced intensity (1) conditioning regimens. Lack of PAMI disease control served as indication for the HSCT in 4 patients, and myelodysplastic syndrome development in one. RESULTS: All 5 patients engrafted, however one patient at day +13 developed hemophagocytic syndrome, followed by graft rejection at day +17. After 5.5 months, a second HSCT was performed from an alternative donor. A further patient at day +116 developed an intense inflammatory syndrome with significant serositis and severe mitral and aortic valve regurgitation, controlled with adalimumab, tacrolimus and prednisone. No other non-infectious inflammatory episodes, or acute or chronic graft-versus-host disease occurred in any patients. At the last follow up (median 2.2 years) all 5 patients have predominantly or complete donor chimerism, adequate immune recovery and are free of any PAMI symptoms. CONCLUSION: Allogeneic HSCT seems to be an effective option to cure cytopenia and severe autoinflammation in PAMI syndrome and may be a curative option for other PSTPIP1-associated inflammatory disorders with poor therapeutic control.

4.
Mol Cell Pediatr ; 7(1): 12, 2020 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-32910272

RESUMO

BACKGROUND: Long-term outcomes of hematopoietic stem cell transplantation (HSCT) in children with juvenile metachromatic leukodystrophy (MLD) have been investigated systematically, while short-term effects of HSCT on the course of the disease remain to be elucidated. RESULTS: In this study, the clinical course was evaluated over the first 24 months following HSCT, conducted at our center in 12 children with juvenile MLD (mean follow-up 6.75 years, range 3-13.5) and compared with 35 non-transplanted children with juvenile MLD. Motor function (GMFM-88 and GMFC-MLD), cognitive function (FSIQ), peripheral neuropathy (tibial nerve conduction velocity), and cerebral changes (MLD-MR severity score) were tested prospectively. Seven children remained neurologically stable over a long period, five exhibited rapid disease progression over the first 12 to 18 months after transplantation. In the latter, time from first gross motor symptoms to loss of independent walking was significantly shorter compared with non-transplanted patients at the same stage of disease (p < 0.02). Positive prognostic factors were good motor function (GMFM = 100%, GMFC-MLD = 0) and a low MR severity score (≤ 17) at the time of HSCT. CONCLUSIONS: Our results show that if disease progression occurs, this happens early on after HSCT and proceeds faster than in non-transplanted children with juvenile MLD, indicating that HSCT may trigger disease progression.

5.
Front Microbiol ; 11: 1899, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32849472

RESUMO

Short rotation coppice (SRC) with metal tolerant plants may attenuate the pollution of excessive elements with potential toxicity in soils, while preserving soil resources and functionality. Here, we investigated effects of 6 years phytomanagement with willow SRC on properties including heavy metal levels, toxicity tested by BioTox, microbial biomass, enzyme activities, and functional gene abundances measured by GeoChip of soils contaminated by As, Cd, Pb and Zn, as compared to the same soils under non-managed mixed grassland representing no intervention treatment (Unt). Though metal total concentrations did not differ by SRC and Unt, SRC soils had lower metal availability and toxicity, higher organic carbon, microbial biomass, phosphatase, urease and protease activities, as compared to Unt soils. Significantly reduced abundances of genes encoding resistances to various metals and antibiotics were observed in SRC, likely attributed to reduced metal selective pressure based on less heavy metal availability and soil toxicity. SRC also significantly reduced abundances of genes involved in nitrogen, phosphorus, and sulfur cycles, possibly due to the willow induced selection. Overall, while the SRC phytomanagement did not reduce the total heavy metal concentrations in soils, it decreased the heavy metal availability and soil toxicity, which in turn led to less metal selective pressure on microbial communities. The SRC phytomanagement also reduced the abundances of nutrient cycling genes from microbial communities, possibly due to intense plant nutrient uptake that depleted soil nitrogen and phosphorus availability, and thus site-specific practices should be considered to improve the soil nutrient supply for phytomanagement plants.

6.
Cancers (Basel) ; 12(7)2020 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-32698364

RESUMO

Immunotherapy with CD19-specific chimeric antigen receptor (CAR-) T cells has shown excellent efficacy in relapsed/refractory B-cell cancers. The in vivo expansion and persistence of CAR-T cells after infusion are important response- and toxicity-determining variables, but diagnostic tools are largely missing. We showed previously for axi-cel that digital PCR (dPCR) is excellently suited to monitoring CAR-T cells in vivo. Here, we aimed to develop an analogous dPCR assay for tisa-cel. To do so, we cloned and sequenced the CAR construct from the lentiviral tisa-cel vector and designed primers and Black hole quencher (BHQ) probes complimentary to sequences present in the FMC63 scFv part of axi-cel (assay A), tisa-cel (T), and both constructs (U = "universal"). In conjunction with excellent specificity, all assays have a detection limit of one single CAR copy, corresponding to a sensitivity of approximately 1 in 5000 cells (0.02%) for 100 ng genomic DNA (for one vector copy per transduced cell). The new universal assay was first validated using patient samples previously quantified with the axi-cel-specific dPCR and thereafter applied to quantify and monitor adoptively transferred axi-cel and tisa-cel T cells in post-infusion samples (peripheral blood, bone marrow, liquor, and ascites). Actual CAR-T counts per µl were calculated, taking into account vector copy and peripheral blood mononuclear cell (PBMC) numbers, and showed very good correlation with flow cytometry results. We conclude that our novel dPCR assay is optimally suited to monitoring tisa-cel and axi-cel CAR-T cells in real-time in various body fluids.

7.
Pediatr Blood Cancer ; 67(9): e28523, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32618429

RESUMO

BACKGROUND: Reduced toxicity conditioning for hematopoietic stem cell transplantation of patients with hemophagocyticlymphohistiocytosis (HLH) results in favorable survival, however at the expense of relevant rates of mixed chimerism. Factors predisposing to mixed chimerism remain to be determined. PROCEDURE: Patients with primary HLH transplanted 2009-2016 after treosulfan- or melphalan-based conditioning regimens were analyzed in a retrospective multicenter study for survival, engraftment, chimerism, and adverse events. Mixed chimerism was considered substantial if < 25% donor chimerism occurred and/or if secondary cell therapy was administered. Donor type, graft source, type of alkylating agent, type of serotherapy, and remission status were analyzed as potential risk factors in a multivariable logistic regression model. RESULTS: Among 60 patients, engraftment was achieved in 95%, and the five-year estimated overall survival rate was 75%. Prevalence of any recipient chimerism was 48%. Substantial recipient chimerism was recorded in 32% of patients. Secondary post-HSCT cell therapy was administered in 30% of patients. A human leukocyte antigen (HLA)-mismatched donor (< 10/10) was the only significant risk factor for the occurrence of substantial recipient chimerism (P = 0.01; odds ratio, 5.8; CI 95%, 1.5-26.3). CONCLUSION: The use of an HLA-matched donor is the most important factor to avoid substantial recipient chimerism following treosulfan -or melphalan-based conditioning in primary HLH.

8.
Blood Adv ; 4(8): 1760-1769, 2020 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-32343795

RESUMO

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 °II-IV (95% confidence interval [CI], 16% to 37%) and 7% for °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.

9.
Stem Cells Dev ; 29(13): 811-822, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32295491

RESUMO

Avascular necrosis (AVN) is a severe complication of immunosuppressant therapy or chemotherapy. A beneficial AVN therapy with core decompression (CD) and intraosseous infusion of mesenchymal stromal cells (MSCs) has been described in adult patients, but there are only few data on MSC applications in pediatric and young adult patients (PYAP). Between 2006 and 2015, 14 AVN lesions of 10 PYAP (6 females) with a median age of 16.9 years (range 8.5-25.8 years) received CD and intraosseous application of autologous MSCs. Data of these patients were analyzed regarding efficacy, safety, and feasibility of this procedure as AVN therapy and compared with a control group of 13 AVN lesions of 11 PYAP (5 females) with a median age of 17.9 years (range 13.5-27.5 years) who received CD only. During the follow-up analysis [MSC group: median 3.1 (1.6-5.8) years after CD; CD group: median 2.0 (1.5-8.5) years after CD], relative lesion sizes (as assessed by magnetic resonance imaging) compared with the initial lesion volume, were significantly lower (P < 0.05) in the MSC group (volume reduction to a median of 18.5%) when compared with the CD group (58.0%). One lesion in the MSC group comprised a complete remission. Size progression was not observed in either group. Clinical improvement (pain, mobility) was not significantly different between the two groups. None of the patients experienced treatment-related adverse effects. CD and additional MSC application was regarded safe, effective, feasible, and superior in reducing the lesion size when compared with CD only. Prospective, randomized clinical trials are needed to further evaluate these findings.

10.
Int Immunopharmacol ; 83: 106371, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32197227

RESUMO

INTRODUCTION: Allogenic hematopoietic stem cell transplantation is a curative option for malignant and non-malignant pediatric diseases. Serotherapy is often employed to avoid graft-versus-host disease (GvHD) on one hand and graft rejection on the other hand. Therapeutic drug monitoring is increasingly used to allow for more precise dosing especially in pediatric patients due to their specific pharmacological characteristics. Application of T-cell directed antibodies is not routinely monitored, but may benefit from more precise dosing regimens. METHODS: Two different preparations of rabbit anti-thymocyte globulin (rATG), Thymoglobuline® and ATG-F (Grafalon®), are frequently used to prevent GvHD in pediatric patients by in vivo T-cell depletion. Total rATG levels and active rATG levels were analyzed prospectively in pediatric patients undergoing HSCT. Clinical and laboratory outcome parameters were recorded. RESULTS: rATG levels were measured in 32 patients, 22 received thymoglobuline and 10 received ATG-F. The median total peak plasma level was 419.0 µg/ml for ATG-F and 60.4 µg/ml for thymoglobuline. For ATG-F, exposure could be predicted from the calculated dose more precisely than for thymoglobuline. Active peak plasma levels neither of ATG-F, nor of thymoglobuline correlated significantly with the number of lymphocytes prior to serotherapy. There was no significant difference in incidence of aGvHD, cGvHD, rejection, mixed chimerism or viral infections in the two cohorts. However, in our cohort, patients with high thymoglobuline exposure showed a compromised reconstitution of T cells. CONCLUSIONS: ATG-F and thymoglobuline show different pharmacological and immunological impact in children, whose clinical significance needs to be investigated in larger cohorts.

11.
Bone Marrow Transplant ; 55(10): 1996-2007, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32203268

RESUMO

Treosulfan-based conditioning prior to allogeneic transplantation has been shown to have myeloablative, immunosuppressive, and antineoplastic effects associated with reduced non-relapse mortality (NRM) in adults. Therefore, we prospectively evaluated the safety and efficacy of treosulfan-based conditioning in children with hematological malignancies in this phase II trial. Overall, 65 children with acute lymphoblastic leukemia (35.4%), acute myeloid leukemia (44.6%), myelodysplastic syndrome (15.4%), or juvenile myelomonocytic leukemia (4.6%) received treosulfan intravenously at a dose of 10 mg/m2/day (7.7%), 12 g/m2/day (35.4%), or 14 g/m2/day (56.9%) according to their individual body surface area in combination with fludarabine and thiotepa. The incidence of complete donor chimerism at day +28 was 98.4% with no primary and only one secondary graft failure. At 36 months, NRM was only 3.1%, while relapse incidence was 21.7%, and overall survival was 83.0%. The cumulative incidence of acute graft-vs.-host disease was 45.3% for grades I-IV and 26.6% for grades II-IV. At 36 months, 25.8% overall and 19.4% moderate/severe chronic graft-vs.-host disease were reported. These data confirm the safe and effective use of treosulfan-based conditioning in pediatric patients with hematological malignancies. Therefore, treosulfan/fludarabine/thiotepa can be recommended for myeloablative conditioning in children with hematological malignancies.

12.
Int J Phytoremediation ; 22(10): 1059-1067, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32075409

RESUMO

This study assessed in situ stabilization combined with phytoexclusion in practical application on agricultural land contaminated strongly, and spatially heterogeneous, with metals (Cd, Pb, and Zn) and As. Single and combined lime marl and phosphate treatments were consecutively planted with two cultivars each of rape, wheat, and barley differing in trace elements (TE) accumulation. The effects on soil acidity, NH4NO3-soluble, and straw and grain TE concentrations were evaluated. The combined fertilizer treatment most effectively reduced metals mobility, but neither amendment mitigated plant TE status, which correlated more with pseudo-total than NH4NO3-soluble TE in soil. The cultivar choice reduced grain Cd by 39 or 21% in barley or wheat, respectively, simultaneously decreased grain Zn, but conversely affected As uptake in wheat grains. The lack of correlations between grain TE concentrations suggests the potential for breeding cultivars with low Cd and As accumulation without causing Zn malnutrition. The cereals had relatively low yields, particularly on highly polluted areas, and only rape and barley grains unexceptionally suited for animal consumption. Agricultural measures and climatic conditions influenced TE mobility. The cultivars' TE uptake varied less than in greenhouse studies, stressing the importance of field studies for an adequate estimation of phytoexclusion potentials.


Assuntos
Metais Pesados/análise , Poluentes do Solo/análise , Oligoelementos , Agricultura , Animais , Biodegradação Ambiental , Produção Agrícola , Solo
13.
Leukemia ; 34(2): 613-624, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31578451

RESUMO

AML SCT-BFM 2007 was the first hematopoietic stem cell transplantation (HCT) trial in Germany to comply with the European Clinical Trials Directive, and aimed to standardize pediatric HCT for acute myeloid leukemia (AML) across centers in Germany, Austria, and the Czech Republic. Children with high-risk features and a good early response achieving a complete first remission (CR-1) and those in CR-2 after a first relapse were stratified to receive HCT from a matched donor after myeloablative conditioning consisting of busulfan, cyclophosphamide, and melphalan. Four-year EFS and OS were 61 and 70%. Cumulative incidence of relapse (CIR) was 22%. TRM was 15% and correlated with age reaching 9% (SE 3%) in children younger than 12 years and 31% (SE 9%) in older children and adolescents. Children with poorly responding primary disease or relapse were allocated to receive early HCT after a cytoreductive regimen with fludarabine, amsacrine, and cytarabine, followed by reduced intensity conditioning and prophylactic donor lymphocyte infusions. Four-year EFS and OS were 49 and 53%. CIR was 38% and TRM 11%. For patients with primary poor response disease, early use of RIC HCT followed by prophylactic DLI can induce long-term remissions in more than 50% (EFS 46% (SE 9%)).

15.
Pediatr Blood Cancer ; 67(2): e28074, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31737984

RESUMO

Pediatric histiocytic sarcoma (HS) clonally related to anteceding leukemia is a rare malignancy with poor outcome. We performed a molecular characterization of HS and the corresponding leukemia by methylation arrays and whole-exome sequencing and found a variety of aberrations in both entities with deletions of CDKN2A/B as a recurrent finding. Furthermore, data from genome-wide mutation analysis from one patient allowed the reconstruction of a sequence of tumorigenesis of leukemia and HS lesions including the acquisition of a putatively activating KRAS frameshift deletion (p.A66fs). Our results provide an insight into the genetic landscape of pediatric HS clonally related to anteceding leukemia.


Assuntos
Análise Mutacional de DNA/métodos , Genoma Humano , Sarcoma Histiocítico/genética , Leucemia Mieloide Aguda/genética , Criança , Inibidor de Quinase Dependente de Ciclina p15/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Mutação da Fase de Leitura , Sarcoma Histiocítico/patologia , Humanos , Leucemia Mieloide Aguda/patologia , Prognóstico , Proteínas Proto-Oncogênicas p21(ras)/genética , Deleção de Sequência , Sequenciamento Completo do Genoma
16.
J Cancer Res Clin Oncol ; 145(11): 2779-2791, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31446489

RESUMO

PURPOSE: To evaluate serum procalcitonin (PCT) and C-reactive protein (CRP) as diagnostic biomarkers of transplant-related adverse events (TRAE) in pediatric patients undergoing hematopoietic stem cell transplantation (HSCT). METHODS: This study analyzed PCT and CRP levels of 214 pediatric patients with a median age of 8.5 years (0.4-17.8 years) undergoing allogeneic HSCT with respect to major TRAE. RESULTS: 26 patients (12.1%) did not experience TRAE (control group), and 188 (87.9%) experienced median 2 (range 1-4) TRAE. Median CRP and PCT were highly and significantly increased during sepsis/SIRS and bacteremia (17.24 mg/dl | 6.30 ng/ml; p < 0.0001 vs. prior values), graft rejection (14.73 mg/dl | 3.20 ng/ml; p < 0.0001), and liver GvHD (6.88 mg/dl | 2.29 ng/ml; p < 0.01). Strong CRP increases and slight/minimal/no PCT increases occurred during fungemia (8.85 mg/dl | 0.72 ng/ml; p < 0.001), intestinal GvHD (8.73 mg/dl | 1.06 ng/ml; p < 0.0001), VOD (10.84 mg/dl | 0.59 ng/ml; p < 0.01), mucositis (8.84 mg/dl | 0.81 ng/ml; p < 0.0001), and viremia (3.62 mg/dl; p < 0.0001 | 0.43 ng/ml; below normal limit). During skin GvHD, CRP and PCT were slightly increased (2.03 mg/dl | 0.93 ng/ml; p < 0.0001). CONCLUSIONS: CRP and PCT did not show congruent changes during TRAE. PCT was a clinically relevant marker for the early detection and differentiation of severe mucositis and sepsis/SIRS and bacteremia during the critical neutropenic period after HSCT. PCT helped to discriminate acute intestinal GvHD from adenovirus viremia and liver GvHD from hepatic VOD. Thus, PCT may be a valuable parameter to enable a prompt and appropriate treatment during these complications, improving patient outcomes.


Assuntos
Bacteriemia/diagnóstico , Proteína C-Reativa/análise , Rejeição de Enxerto/diagnóstico , Doença Enxerto-Hospedeiro/diagnóstico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Pró-Calcitonina/sangue , Sepse/diagnóstico , Adolescente , Bacteriemia/sangue , Bacteriemia/etiologia , Biomarcadores/sangue , Estudos de Casos e Controles , Criança , Pré-Escolar , Diagnóstico Precoce , Feminino , Seguimentos , Rejeição de Enxerto/sangue , Rejeição de Enxerto/etiologia , Doença Enxerto-Hospedeiro/sangue , Doença Enxerto-Hospedeiro/etiologia , Neoplasias Hematológicas/patologia , Neoplasias Hematológicas/terapia , Humanos , Lactente , Masculino , Prognóstico , Estudos Retrospectivos , Sepse/sangue , Sepse/etiologia , Transplante Homólogo
17.
Mol Genet Metab ; 128(1-2): 84-91, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31375398

RESUMO

OBJECTIVE: To provide recommendations for managing hypersensitivity adverse events (HAEs) to an injectable enzyme substitution therapy (pegvaliase, a PEGylated phenylalanine ammonia lyase enzyme) in adult patients with phenylketonuria (PKU). METHODS: Eight European academic immunology experts with a broad range of experience in hypersensitivity, anaphylaxis, and/or drug reactions, and two geneticists from the USA with pegvaliase experience convened for two advisory board meetings. Efficacy, safety, and immunological profile of pegvaliase were discussed with the objective of developing recommendations for the clinical management of HAEs associated with pegvaliase treatment. RESULTS: Based on available immunogenicity data, it was concluded that pegvaliase induces a Type III hypersensitivity reaction, causing HAEs with peak event rates during induction/titration and a decline over time during maintenance therapy. The decline in HAEs with longer duration of therapy was considered to likely be driven by anti-drug antibody affinity maturation, reduced immune complex formation, and decreased complement activation over time. Immunology and PKU experts unanimously supported that the use of an induction, titration, and maintenance dosing regimen and implementation of several risk mitigation strategies contributed to the improvement of tolerability over time. Key risk mitigation strategies utilized in the Phase 3 clinical trials such as premedication with H1-receptor antagonists, allowance for a longer titration period after an HAE, patient education, and requirement to carry auto-injectable adrenaline (epinephrine) should be continued in clinical practice. A tool for administration of auto-injectable adrenaline in patients using pegvaliase was suggested. It was added that after the occurrence of a severe HAE a temporary dose reduction is more likely to improve tolerability than treatment interruption. CONCLUSIONS: Overall, it was agreed that pegvaliase has a generally tolerable safety profile in adults with PKU. Importantly, the risk mitigation strategies utilized in the clinical trials were considered to support the continued use of key strategies for management in the commercial setting, such as a slow induction/titration dosing paradigm and premedication with H1-receptor antagonists. However, physicians and patients need to be aware of the risk of HAEs associated with pegvaliase; presence of a trained observer during early treatment may be beneficial in certain circumstances, and a requirement to carry auto-injectable adrenaline is recommended. Because pegvaliase offers the possibility to normalize diet, while maintaining blood phenylalanine within the recommended therapeutic range, safe use of this medication in the clinical setting is important. Ongoing monitoring of long-term clinical safety of patients on pegvaliase treatment in the commercial setting was recommended.


Assuntos
Gerenciamento Clínico , Hipersensibilidade/prevenção & controle , Fenilalanina Amônia-Liase/efeitos adversos , Fenilalanina Amônia-Liase/uso terapêutico , Fenilcetonúrias/tratamento farmacológico , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico , Anticorpos/sangue , Ensaios Clínicos Fase III como Assunto , Terapia de Reposição de Enzimas , Humanos , Fenilalanina/sangue , Fenilcetonúrias/sangue , Fatores de Tempo
18.
Bone Marrow Transplant ; 54(11): 1847-1858, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31089287

RESUMO

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.


Assuntos
Seleção do Doador , Haplótipos , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Polimorfismo Genético , Leucemia-Linfoma Linfoblástico de Células Precursoras , Receptores KIR/genética , Telômero/genética , Condicionamento Pré-Transplante , Adolescente , Adulto , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Taxa de Sobrevida
19.
Pediatr Nephrol ; 34(7): 1269-1275, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30843115

RESUMO

BACKGROUND: During the last two decades, there has been a worldwide increase in frequency and severity of infections with Clostridium difficile (CDI). Solid organ transplant (SOT) recipients receiving immunosuppressing medications are especially at risk. METHODS: We collected data from immunocompromised pediatric patients, including kidney and liver transplant recipients, at our tertiary pediatric care center in Germany. For this, we performed a retrospective review of institutional databases and analyzed data from all children who underwent diagnostic tests for CDI in a 3-year study period. RESULTS: A total of 797 diagnostic tests in 343 patients were performed. We found 104 infection episodes in 69 patients (42% female, ages 12 days-20 years). Children after SOT accounted for 20% of all detected CDI patients in our series. Median time of CDI onset after transplantation was 588 days. Overall antibiotic exposure was identified as the major risk factor, particularly in immunocompromised children after SOT (exposure in > 95% of all cases). CONCLUSIONS: The occurrence of CDI in the pediatric SOT population contributes to a greater length of stay and higher hospital charges. However, only very few severe complications from CDI were observed in our cohort. A potentially fulminant course of CDI can be prevented in most cases if timely diagnosis and treatment are carried out.


Assuntos
Enterocolite Pseudomembranosa/etiologia , Imunossupressão/efeitos adversos , Transplante de Rim/efeitos adversos , Transplante de Fígado/efeitos adversos , Adolescente , Antibacterianos/efeitos adversos , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Recidiva , Estudos Retrospectivos , Fatores de Risco , Adulto Jovem
20.
Mol Ther ; 27(5): 933-946, 2019 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-30879952

RESUMO

Chimeric antigen receptor (CAR) engineering of T cells allows one to specifically target tumor cells via cell surface antigens. A candidate target in Ewing sarcoma is the ganglioside GD2, but heterogeneic expression limits its value. Here we report that pharmacological inhibition of Enhancer of Zeste Homolog 2 (EZH2) at doses reducing H3K27 trimethylation, but not cell viability, selectively and reversibly induces GD2 surface expression in Ewing sarcoma cells. EZH2 in Ewing sarcoma cells directly binds to the promoter regions of genes encoding for two key enzymes of GD2 biosynthesis, and EZH2 inhibition enhances expression of these genes. GD2 surface expression in Ewing sarcoma cells is not associated with distinct in vitro proliferation, colony formation, chemosensitivity, or in vivo tumorigenicity. Moreover, disruption of GD2 synthesis by gene editing does not affect its in vitro behavior. EZH2 inhibitor treatment sensitizes Ewing sarcoma cells to effective cytolysis by GD2-specific CAR gene-modified T cells. In conclusion, we report a clinically applicable pharmacological approach for enhancing efficacy of adoptively transferred GD2-redirected T cells against Ewing sarcoma, by enabling recognition of tumor cells with low or negative target expression.


Assuntos
Proteína Potenciadora do Homólogo 2 de Zeste/genética , Gangliosídeos/genética , Receptores de Antígenos Quiméricos/genética , Sarcoma de Ewing/tratamento farmacológico , Antígenos de Superfície/efeitos dos fármacos , Antígenos de Superfície/genética , Benzamidas/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Gangliosídeos/biossíntese , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Imunoterapia/métodos , Imunoterapia Adotiva/métodos , Indóis/farmacologia , Regiões Promotoras Genéticas/genética , Piridonas/farmacologia , Receptores de Antígenos Quiméricos/imunologia , Sarcoma de Ewing/genética , Sarcoma de Ewing/imunologia , Sarcoma de Ewing/patologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia
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