Parvovirus B19 způsobuje klasické dětské exantémové onemocnění známé jako 5. dětská nemoc (erythema infectiosum) se sezónním výskytem, zpravidla se zvýrazněním ve 3až 5letých cyklech. Výrazně vyšší incidence je pozorována celosvětově od roku 2023. stejně jako u předchozích nápadných vln dalších virových onemocnění (např. rsV a chřipky) se i v tomto případě nabízí souvislost s covidovou pandemií (skokové promoření po 2letých sociálních restrikcích). Článek přináší pohled hematologa, demonstrovaný na souboru pacientů se symptomatickou parvovirovou infekcí prokázanou metodou pcr na klinice dětské hematologie a onkologie 2. lF uk a Fn Motol za období 12 let (02/2012–06/2024). cílem není epidemiologická analýza, ale zviditelnění problematiky v českém periodiku a zdokumentování pestrosti hematologické manifestace této infekce.
Parvovirus B19 is the causative agent of classical childhood illness known as the 5th disease or erythema infectiosum. the occurrence has a seasonal character, with more dominant waves every 3 to 5 years. remarkably higher incidence since 2023 is observed globally. similarly to recent distinct waves od rsV and influenza, even in this case we can suspect a connection with covid pandemic (rapid contagion after 2 years of social restrictions). the article describes a cohort of patients with pcr confirmed symptomatic parvovirus B19 infection during a period of 12 years (02/2012-06/2024) at the department of pediatric Hematology and oncology, Motol university Hospital. We do not aim at thorough epidemiological analysis, but rather focus on bringing the topic to the czech pediatric community and describe hematological variety of parvovirus B19 infection.
- MeSH
- aplastická anemie etiologie MeSH
- dítě MeSH
- erythema infectiosum * diagnóza epidemiologie farmakoterapie MeSH
- hemolytické anemie diagnóza etiologie MeSH
- imunosupresivní léčba MeSH
- lidé MeSH
- lidský parvovirus B19 * patogenita MeSH
- mladiství MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
Measurable residual disease (MRD) monitoring in childhood acute myeloid leukemia (AML) is used to assess response to treatment and for early detection of imminent relapse. In childhood AML, MRD is typically evaluated using flow cytometry, or by quantitative detection of leukemia-specific aberrations at the mRNA level. Both methods, however, have significant limitations. Recently, we demonstrated the feasibility of MRD monitoring in selected subgroups of AML at the genomic DNA (gDNA) level. To evaluate the potential of gDNA-based MRD monitoring across all AML subtypes, we conducted a comprehensive analysis involving 133 consecutively diagnosed children. Integrating next-generation sequencing into the diagnostic process, we identified (presumed) primary genetic aberrations suitable as MRD targets in 97% of patients. We developed patient-specific quantification assays and monitored MRD in 122 children. The gDNA-based MRD monitoring via quantification of primary aberrations with a sensitivity of at least 10-4 was possible in 86% of patients; via quantification with sensitivity of 5 × 10-4, of secondary aberrations, or at the mRNA level in an additional 8%. Importantly, gDNA-based MRD exhibited independent prognostic value at early time-points in patients stratified to intermediate-/high-risk treatment arms. Our study demonstrates the broad applicability, feasibility, and clinical significance of gDNA-based MRD monitoring in childhood AML.
- MeSH
- akutní myeloidní leukemie * diagnóza genetika terapie MeSH
- dítě MeSH
- genomika MeSH
- kohortové studie MeSH
- lidé MeSH
- messenger RNA genetika MeSH
- prognóza MeSH
- průtoková cytometrie MeSH
- recidiva MeSH
- reziduální nádor diagnóza genetika MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: The BCR::ABL1 is a hallmark of chronic myeloid leukemia (CML) and is also found in acute lymphoblastic leukemia (ALL). Most genomic breaks on the BCR side occur in two regions - Major and minor - leading to p210 and p190 fusion proteins, respectively. METHODS: By multiplex long-distance PCR or next-generation sequencing technology we characterized the BCR::ABL1 genomic fusion in 971 patients (adults and children, with CML and ALL: pediatric ALL: n = 353; pediatric CML: n = 197; adult ALL: n = 166; adult CML: n = 255 patients) and designed "Break-App" web tool to allow visualization and various analyses of the breakpoints. Pearson's Chi-Squared test, Kolmogorov-Smirnov test and logistic regression were used for statistical analyses. RESULTS: Detailed analysis showed a non-random distribution of breaks in both BCR regions, whereas ABL1 breaks were distributed more evenly. However, we found a significant difference in the distribution of breaks between CML and ALL. We found no association of breakpoints with any type of interspersed repeats or DNA motifs. With a few exceptions, the primary structure of the fusions suggests non-homologous end joining being responsible for the BCR and ABL1 gene fusions. Analysis of reciprocal ABL1::BCR fusions in 453 patients showed mostly balanced translocations without major deletions or duplications. CONCLUSIONS: Taken together, our data suggest that physical colocalization and chromatin accessibility, which change with the developmental stage of the cell (hence the difference between ALL and CML), are more critical factors influencing breakpoint localization than presence of specific DNA motifs.
- MeSH
- akutní lymfatická leukemie * genetika patologie MeSH
- bcr-abl fúzní proteiny * genetika MeSH
- body zlomu chromozomu * MeSH
- chronická myeloidní leukemie * genetika patologie MeSH
- dítě MeSH
- dospělí MeSH
- lidé MeSH
- vysoce účinné nukleotidové sekvenování MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- dopisy MeSH
Steroids are a mainstay in the treatment of acute lymphoblastic leukaemia (ALL) in children and adolescents; however, their use can cause clinically significant steroid-related neuropsychiatric symptoms (SRNS). As current knowledge on SRNS during ALL treatment is limited, we mapped the phenotypes, occurrence and treatment strategies using a database created by the international Ponte di Legno Neurotoxicity Working Group including data on toxicity in the central nervous system (CNS) in patients treated with frontline ALL protocols between 2000 and 2017. Ninety-four of 1813 patients in the CNS toxicity database (5.2%) experienced clinically significant SRNS with two peaks: one during induction and one during intensification phase. Dexamethasone was implicated in 86% of SRNS episodes. The most common symptoms were psychosis (52%), agitation (44%) and aggression (31%). Pharmacological treatment, mainly antipsychotics and benzodiazepines, was given to 87% of patients while 38% were hospitalised due to their symptoms. Recurrence of symptoms was reported in 29% of patients and two previously healthy patients required ongoing pharmacological treatment at the last follow up. Awareness of SRNS during ALL treatment and recommendation on treatment strategies merit further studies and consensus.
- MeSH
- akutní lymfatická leukemie * farmakoterapie MeSH
- dexamethason škodlivé účinky terapeutické užití aplikace a dávkování MeSH
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- neurotoxické syndromy etiologie MeSH
- předškolní dítě MeSH
- protokoly protinádorové kombinované chemoterapie škodlivé účinky terapeutické užití MeSH
- steroidy terapeutické užití škodlivé účinky MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- pozorovací studie MeSH
BACKGROUND AND OBJECTIVE: Inotuzumab ozogamicin is an antibody-drug conjugate approved for treating relapsed/refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in adults. Pediatric pharmacokinetic data of inotuzumab ozogamicin are lacking. This study is the first to examine the population pharmacokinetics of inotuzumab ozogamicin in pediatric patients with relapsed/refractory BCP-ALL. METHODS: From 531 adult patients with B-cell non-Hodgkin's lymphoma, 234 adult patients with BCP-ALL, and 53 pediatric patients with BCP-ALL, 8924 inotuzumab ozogamicin serum concentrations were analyzed using non-linear mixed-effects modeling. A published adult inotuzumab ozogamicin population-pharmacokinetic model, a two-compartment model with linear and time-dependent clearance, was adapted to describe the pediatric data. RESULTS: Modifications in this analysis, compared to the published adult model, included: (i) re-estimating pharmacokinetic parameters and covariate effects; (ii) modifying covariate representation; and (iii) introducing relevant pediatric covariate effects (age on the decay coefficient of time-dependent clearance and ALL effect (disease type and/or different bioanalytical analysis methods) on initial values of time-dependent clearance). For patients with relapsed/refractory BCP-ALL, increasing age was associated with a decreasing decay coefficient of time-dependent clearance, reflecting that the target-mediated drug clearance declines more rapidly in children. In pediatric BCP-ALL, the median [interquartile range] cumulative area under the concentration-time curve was significantly higher among responders (n = 42) versus non-responders (n = 10) at the end of the first cycle (26.1 [18.9-35.0] vs 10.1 [9.19-16.1], × 103 ng*h/mL, p < 0.001). From simulations performed at the recommended pediatric phase II dose, inotuzumab ozogamicin exposure reached a similar level as observed in responding pediatric trial participants. CONCLUSIONS: The pharmacokinetic profile of inotuzumab ozogamicin in pediatric patients with relapsed/refractory BCP-ALL was well described in this study. No dose adjustment is required clinically for pediatric patients with BCP-ALL based on the simulated inotuzumab ozogamicin exposure at the recommended pediatric phase II dose, promising efficacy and acceptable tolerability.
- MeSH
- biologické modely MeSH
- dítě MeSH
- dospělí MeSH
- inotuzumab ozogamicin * farmakokinetika aplikace a dávkování MeSH
- kojenec MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- pre-B-buněčná leukemie * farmakoterapie krev MeSH
- předškolní dítě MeSH
- protinádorové látky imunologicky aktivní * farmakokinetika aplikace a dávkování terapeutické užití MeSH
- recidiva MeSH
- senioři MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- kojenec MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
BACKGROUND: T-cell acute lymphoblastic leukemia (T-ALL) represents a rare and clinically and genetically heterogeneous disease that constitutes 10-15% of newly diagnosed pediatric ALL cases. Despite improved outcomes of these children, the survival rate after relapse is extremely poor. Moreover, the survivors must also endure the acute and long-term effects of intensive therapy. Although recent studies have identified a number of recurrent genomic aberrations in pediatric T-ALL, none of the changes is known to have prognostic significance. The aim of our study was to analyze the cytogenomic changes and their various combinations in bone marrow cells of children with T-ALL and to correlate our findings with the clinical features of the subjects and their treatment responses. RESULTS: We performed a retrospective and prospective comprehensive cytogenomic analysis of consecutive cohort of 66 children (46 boys and 20 girls) with T-ALL treated according to BFM-based protocols and centrally investigated cytogenetics and immunophenotypes. Using combinations of cytogenomic methods (conventional cytogenetics, FISH, mFISH/mBAND, arrayCGH/SNP and MLPA), we identified chromosomal aberrations in vast majority of patients (91%). The most frequent findings involved the deletion of CDKN2A/CDKN2B genes (71%), T-cell receptor (TCR) loci translocations (27%), and TLX3 gene rearrangements (23%). All chromosomal changes occurred in various combinations and were rarely found as a single abnormality. Children with aberrations of TCR loci had a significantly better event free (p = 0.0034) and overall survival (p = 0.0074), all these patients are living in the first complete remission. None of the abnormalities was an independent predictor of an increased risk of relapse. CONCLUSIONS: We identified a subgroup of patients with TCR aberrations (both TRA/TRD and TRB), who had an excellent prognosis in our cohort with 5-year EFS and OS of 100%, regardless of the presence of other abnormality or the translocation partner. Our data suggest that escalation of treatment intensity, which may be considered in subsets of T-ALL is not needed for nonHR (non-high risk) patients with TCR aberrations.
- Publikační typ
- časopisecké články MeSH
- MeSH
- akutní lymfatická leukemie * farmakoterapie genetika MeSH
- bcr-abl fúzní proteiny genetika MeSH
- lidé MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- dopisy MeSH
- práce podpořená grantem MeSH
Problematika očkování pacientů se sekundárním imunodeficitem po chemoterapii, imunosupresivní léčbě a po transplantaci krvetvorných kmenových buněk je dlouhodobě studována. Po vlastních klinických zkušenostech s očkováním a pravidelným vyšetřováním postvakcinační imunity u těchto rizikových pacientů jsme vytvořili po společné dohodě s dětskými hematology a onkology doporučení, jak postupovat v bezpečné, časné a efektivní obnově imunitní ochrany vůči závažným infekčním onemocněním.
The issue of vaccination of patients with secondary immunodeficiency after chemotherapy, immunosuppressive treatment and after hematopoietic stem cell transplantation has been studied for a long time. After our own clinical experience with vaccination and regular follow-up of post-vaccination immunity in these high-risk patients, we created, by collective agreement with pediatric hemato-oncologists, recommendation on how to proceed to safe, early and effective restoration of immune protection against serious infectious diseases.
- MeSH
- dítě MeSH
- farmakoterapie MeSH
- hematologické nádory terapie MeSH
- imunosupresivní léčba škodlivé účinky MeSH
- lidé MeSH
- nádory terapie MeSH
- očkovací schéma * MeSH
- syndromy imunologické nedostatečnosti * chemicky indukované MeSH
- transplantace kmenových buněk škodlivé účinky MeSH
- vakcinace * MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- Publikační typ
- přehledy MeSH
- směrnice pro lékařskou praxi MeSH
Tisagenlecleucel (tisa-cel) is a CD19-specific CAR-T cell product approved for the treatment of relapsed/refractory (r/r) DLBCL or B-ALL. We have followed a group of patients diagnosed with childhood B-ALL (n = 5), adult B-ALL (n = 2), and DLBCL (n = 25) who were treated with tisa-cel under non-clinical trial conditions. The goal was to determine how the intensive pretreatment of patients affects the produced CAR-T cells, their in vivo expansion, and the outcome of the therapy. Multiparametric flow cytometry was used to analyze the material used for manufacturing CAR-T cells (apheresis), the CAR-T cell product itself, and blood samples obtained at three timepoints after administration. We present the analysis of memory phenotype of CD4/CD8 CAR-T lymphocytes (CD45RA, CD62L, CD27, CD28) and the expression of inhibitory receptors (PD-1, TIGIT). In addition, we show its relation to the patients' clinical characteristics, such as tumor burden and sensitivity to prior therapies. Patients who responded to therapy had a higher percentage of CD8+CD45RA+CD27+ T cells in the apheresis, although not in the produced CAR-Ts. Patients with primary refractory aggressive B-cell lymphomas had the poorest outcomes which was characterized by undetectable CAR-T cell expansion in vivo. No clear correlation of the outcome with the immunophenotypes of CAR-Ts was observed. Our results suggest that an important parameter predicting therapy efficacy is CAR-Ts' level of expansion in vivo but not the immunophenotype. After CAR-T cells' administration, measurements at several timepoints accurately detect their proliferation intensity in vivo. The outcome of CAR-T cell therapy largely depends on biological characteristics of the tumors rather than on the immunophenotype of produced CAR-Ts.
