RESUMO
B-cell acute lymphoblastic leukemia (B-ALL), a prevalent malignancy predominantly affecting children, poses challenges such as drug resistance and cytotoxicity despite available treatment methods. The persistence of these challenges underscores the necessity for innovative therapeutic approaches to enhance efficacy. Natural compounds derived from plants, recognized for their potential to inhibit cancer cell growth, have drawn attention. Trifolium pratense extract, known for its significant anticancer properties in previous studies, was the focus of this investigation. This experimental study aimed to explore the impact of T. pratense extract on apoptosis and autophagy in NALM-6 cells. The cells were exposed to varying concentrations of the extract at specific time intervals, with viability and metabolic activity assessed using Trypan blue exclusion and MTT assays. Flow cytometry was employed to evaluate apoptosis using Annexin V/PI staining and ROS production using DCFH-DA staining. Real-time PCR was used to quantify gene expression related to apoptosis, autophagy, and oxidative stress, with data analysis performed using GraphPad PRISM software. Trifolium pratense extract demonstrated the capacity to induce apoptosis, autophagy, and significantly increase ROS production in NALM-6 cells. These effects were facilitated by the upregulation of corresponding genes. The MTT assay revealed an IC50 of 231 µg/mL at 48 h, and Flow cytometry analysis showed a 51.8% increase in apoptosis in this cell line. Overall, this study emphasizes the effectiveness of T. pratense extract in inducing autophagy and apoptosis pathways in NALM-6 cells derived from B-cell acute lymphoblastic leukemia, suggesting its potential as a candidate for further investigation as a supplement in ALL treatment.
Assuntos
Apoptose , Autofagia , Extratos Vegetais , Trifolium , Trifolium/química , Humanos , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Extratos Vegetais/farmacologia , Linhagem Celular Tumoral , Espécies Reativas de Oxigênio/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Antineoplásicos Fitogênicos/farmacologiaRESUMO
PURPOSE: The current study aims to investigate the significance of N6-methyladenosine (m6A) methylationrelated genes in the clinical prognosis of childhood relapsed B-cell acute lymphoblastic leukemia (B-ALLL) patient. METHODS: Transcriptome data and corresponding clinical data on m6A methylation-related genes (including 20 genes) were obtained from the Therapeutically Applicable Research To Generate Effective Treatments (TARGET) database. RESULTS: The bone marrow (BM) samples of 134 newly diagnosed (naive) and 116 relapsed B-ALL from TARGET were enrolled in the current study. Three genes (FTO, HNRNPC, RBM15B) showed significant up-regulation in relapsed B-ALL compared with that in naive B-ALL.The three genes had a significantly worse survival (P < 0.05). The LASSO Cox regression model was used to select the most predictive genes as prognostic indicators, and YTHDC1 and FTO were identified as prognostic factors for relapsed B-ALL. Finally, the results of multivariate regression analysis showed that the risk score of m6A methylation-related genes was an independent prognostic factor in relapsed B-ALL (P < 0.05). CONCLUSION: We found that the expression levels of m6A methylation-related genes were different in naive and relapsed patients with B-ALL and correlated with survival and prognosis.This implies that m6A methylation-related genes may be promising prognostic indicators or therapeutic targets for relapsed B-ALL.
Assuntos
Adenosina , Dioxigenase FTO Dependente de alfa-Cetoglutarato , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Fatores de Processamento de RNA , Proteínas de Ligação a RNA , Humanos , Prognóstico , Adenosina/análogos & derivados , Adenosina/genética , Criança , Feminino , Masculino , Proteínas de Ligação a RNA/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidade , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Fatores de Processamento de RNA/genética , Ribonucleoproteínas Nucleares Heterogêneas Grupo C/genética , Metilação , Pré-Escolar , Transcriptoma , Regulação para Cima , Biomarcadores Tumorais/genética , Recidiva , Recidiva Local de Neoplasia/genética , Adolescente , Proteínas do Tecido NervosoAssuntos
Inotuzumab Ozogamicina , Necrose , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Feminino , Humanos , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/uso terapêutico , Medula Óssea/patologia , Inflamação , Necrose/induzido quimicamente , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Pessoa de Meia-IdadeRESUMO
The t(1;19) (q23;p13) TCF3::PBX1 is a well-described, recurring chromosomal abnormality in B-acute lymphoblastic leukaemia (B-ALL) that has historically been associated with a worse prognosis in paediatric patients. Gene expression profiling has demonstrated that TCF3::PBX1 results in a distinct subtype of B-ALL, leading to its recognition in the most recent WHO and ICC classifications. Though initially believed to be a poor prognostic sign in the adult population, emerging evidence suggests its presence may instead be intermediate or even favourable in B-ALL. However, adults with TCF3::PBX1 are typically younger and often qualify for treatment with paediatric-inspired regimens. Thus, the prognostic significance in this population remains unclear. This translocation appears to be very rare in older adults with B-ALL and its predictive and prognostic nature in this population is unknown. Herein, we explore a case of this translocation occurring in a patient in her 70s. She initially presented to the emergency department with abdominal pain and thrombocytopenia and was subsequently diagnosed with B-ALL. In addition to t(1;19) (q23;p13), a pathologic mutation in the CBL gene was identified. CBL mutations have been implicated in cancer progression and are mostly described in paediatric B-ALL. She was treated with modified Ph-negative EWALL induction (Vincristine, Idarubicin, dexamethasone) and achieved a complete remission. However, she subsequently experienced an early relapse and was refractory to targeted therapy with blinatumomab. After treatment with inotuzumab ozogamicin, she achieved a second complete remission. Unfortunately, she then suffered a central nervous system (CNS) relapse and passed away from complications of her disease. This case serves as an example of the heterogeneous nature of B-ALL. It demonstrates that patients with ostensibly favourable prognostic factors may experience poor response rates to traditional chemotherapy as well as targeted salvage agents. It also illustrates the challenges of treating B-ALL in the elderly population.
Assuntos
Proteínas de Fusão Oncogênica , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Proteínas Proto-Oncogênicas c-cbl , Translocação Genética , Humanos , Feminino , Idoso , Proteínas de Fusão Oncogênica/genética , Proteínas Proto-Oncogênicas c-cbl/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Mutação , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cromossomos Humanos Par 19/genética , Cromossomos Humanos Par 1/genéticaRESUMO
Blinatumomab has emerged as a promising component of first-line therapy for acute B-cell precursor lymphoblastic leukemia (BCP-ALL), bolstering treatment efficacy. To mitigate CD19 selection pressure and reduce the incidence of blinatumomab-associated toxicities, pre-treatment chemotherapy is recommended before administering blinatumomab. From September 2022 to December 2023, we conducted a single-arm, multicenter, phase 2 trial (NCT05557110) in newly diagnosed Philadelphia chromosome-negative BCP-ALL (Ph-negative BCP-ALL) patients. Participants received induction treatment with reduced-dose chemotherapy (RDC), comprising idarubicin, vindesine, and dexamethasone over 7 days, followed by 2 weeks of blinatumomab. Those failing to achieve composite complete remission (CRc) received an additional 2 weeks of blinatumomab. The primary endpoint was the CRc rate post initial induction treatment. Of the 35 enrolled patients, 33 (94%) achieved CRc after 2 weeks of blinatumomab, with 30 (86%) achieving measurable residual disease (MRD) negativity. Two patients extended blinatumomab to 4 weeks. With either 2 or 4 weeks of blinatumomab treatment, all patients achieved CR (35/35) and 89% (31/35) were MRD negativity. The median time to CR was 22 days. Immune effector cell-associated neurotoxicity syndrome was limited (14%, all grade 1). Non-hematological adverse events of grade 3 or higher included pneumonia (17%), sepsis (6%), and cytokine release syndrome (9%). With a median follow-up of 11.5 months, estimated 1-year overall survival and 1-year progression-free survival rates were 97.1% and 82.2%, respectively. These findings affirm that RDC followed by blinatumomab is an effective and well-tolerated induction regimen for newly diagnosed Ph-negative BCP-ALL, supporting a shift towards less intensive and more targeted therapeutic approaches. Trial registration: https://www.clinicaltrials.Gov . Identifier NCT05557110.
Assuntos
Anticorpos Biespecíficos , Protocolos de Quimioterapia Combinada Antineoplásica , Quimioterapia de Indução , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Humanos , Anticorpos Biespecíficos/uso terapêutico , Anticorpos Biespecíficos/administração & dosagem , Anticorpos Biespecíficos/efeitos adversos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Adulto Jovem , Quimioterapia de Indução/métodos , Idoso , Adolescente , Dexametasona/administração & dosagem , Dexametasona/uso terapêutico , Dexametasona/efeitos adversos , Indução de RemissãoRESUMO
The dysregulation of alternative splicing (AS) is increasingly recognized as a pivotal player in the pathogenesis, progression, and treatment resistance of B-cell acute lymphoblastic leukemia (B-ALL). Despite its significance, the clinical implications of AS events in B-ALL remain largely unexplored. This study developed a prognostic model based on 18 AS events (18-AS), derived from a meticulous integration of bioinformatics methodologies and advanced machine learning algorithms. The 18-AS signature observed in B-ALL distinctly categorized patients into different groups with significant differences in immune infiltration, V(D)J rearrangement, drug sensitivity, and immunotherapy outcomes. Patients classified within the high 18-AS group exhibited lower immune infiltration scores, poorer chemo- and immune-therapy responses, and worse overall survival, underscoring the model's potential in refining therapeutic strategies. To validate the clinical applicability of the 18-AS, we established an SF-AS regulatory network and identified candidate drugs. More importantly, we conducted in vitro cell proliferation assays to confirm our analysis, demonstrating that the High-18AS cell line (SUP-B15) exhibited significantly enhanced sensitivity to Dasatinib, Dovitinib, and Midostaurin compared to the Low-18AS cell line (REH). These findings reveal AS events as novel prognostic biomarkers and therapeutic targets, advancing personalized treatment strategies in B-ALL management.
Assuntos
Processamento Alternativo , Humanos , Processamento Alternativo/genética , Prognóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Feminino , Linhagem Celular Tumoral , Masculino , Biologia Computacional/métodosRESUMO
Extracellular vesicles (EVs) are heterogeneous, phospholipid membrane enclosed particles that are secreted by healthy and cancerous cells. EVs are present in diverse biological fluids and have been associated with the severity of diseases, which indicates their potential as biomarkers for diagnosis, prognosis and as therapeutic targets. This study investigated the phenotypic characteristics of EVs derived from peripheral blood (PB) and bone marrow (BM) in pediatric patients with B-cell acute lymphoblastic leukemia (B-ALL) during different treatment stages. PB and BM plasma were collected from 20 B-ALL patients at three time points during induction therapy, referred to as: diagnosis baseline (D0), day 15 of induction therapy (D15) and the end of the induction therapy (D35). In addition, PB samples were collected from 10 healthy children at a single time point. The EVs were measured using CytoFLEX S flow cytometer. Calibration beads were employed to ensure accurate size analysis. The following, fluorescent-labeled specific cellular markers were used to label the EVs: Annexin V (phosphatidylserine), CD235a (erythrocyte), CD41a (platelet), CD51 (endothelial cell), CD45 (leukocyte), CD66b (neutrophil), CD14 (monocyte), CD3 (T lymphocyte), CD19, CD34 and CD10 (B lymphoblast/leukemic blast). Our results demonstrate that B-ALL patients had a marked production of EV-CD51/61+, EV-CD10+, EV-CD19+ and EV-CD10+CD19+ (double-positive) with a decrease in EV-CD41a+ on D0. However, the kinetics and signature of production during induction therapy revealed a clear decline in EV-CD10+ and EV-CD19+, with an increase of EV-CD41a+ on D35. Furthermore, B-ALL patients showed a complex biological network, exhibiting distinct profiles on D0 and D35. Interestingly, fold change and ROC curve analysis demonstrated that EV-CD10+CD19+ were associated with B-ALL patients, exhibited excellent clinical performance and standing out as a potential diagnostic biomarker. In conclusion, our data indicate that EVs represent a promising field of investigation in B-ALL, offering the possibility of identifying potential biomarkers and therapeutic targets.
Assuntos
Medula Óssea , Vesículas Extracelulares , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Humanos , Criança , Vesículas Extracelulares/metabolismo , Feminino , Masculino , Pré-Escolar , Leucemia-Linfoma Linfoblástico de Células Precursoras B/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Medula Óssea/metabolismo , Adolescente , Estudo de Prova de Conceito , Biomarcadores Tumorais , LactenteRESUMO
BACKGROUND: Blinatumomab is a CD3/CD19-directed bispecific T-cell engager molecule that engages T cells to lyse CD19-expressing B cells. Based on a multicenter, open-label, phase 3, randomized clinical trial (Clinical Trials ID: NCT02393859), we aimed to evaluate the cost-effectiveness (CE) of blinatumomab compared to standard consolidation chemotherapy (SC) for the treatment of pediatric patients with high-risk first-relapsed Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukemia (B-ALL) from a Mexico healthcare payer perspective. METHODS: A decision-analytic model, a partitioned survival model, was used to estimate the life-years (LYs) and costs over a lifetime horizon. We assumed that patients who remained alive beyond a 5-year period were cured. To account for the lingering impacts of cancer treatment, an excess mortality rate was incorporated into the model. Event-free survival (EFS) and overall survival (OS) were estimated by fitting mixture-cure and standard parametric survival distributions to the time-to-event data from the phase 3 trial. The model accounted for treatment costs, adverse event costs, follow-up costs, subsequent allogeneic hematopoietic stem cell transplantation (alloHSCT) costs, and subsequent treatment costs. RESULTS: Blinatumomab was associated with a lifetime gained of 5.11 years at an incremental cost of $621,111 MXN, relative to SC. The ICER for blinatumomab vs Standard of care was estimated to be $121,526 MXN/LY gained in the base case. Cost-effectiveness was sensitive to varying the time horizon. Blinatumomab had a probability of 99â¯% of being cost-effective, relative to SC, at the willingness to pay threshold defined in Mexico. LIMITATIONS: Health-related quality of life values were not included in the analysis and therefore we did not estimate the quality-adjusted life-years gained. CONCLUSIONS: Blinatumomab was associated with greater benefit in terms of OS and EFS relative to SC. Probabilistic, deterministic, and scenario analyses indicate that blinatumomab represents the best value for money. Therefore, blinatumomab administered as part of consolidation therapy in B-ALL pediatric patients with high-risk first relapse is a cost-effective option.
Assuntos
Anticorpos Biespecíficos , Análise Custo-Benefício , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Humanos , Anticorpos Biespecíficos/economia , Anticorpos Biespecíficos/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/economia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidade , Criança , México , Feminino , Masculino , Anos de Vida Ajustados por Qualidade de Vida , Adolescente , Pré-Escolar , Quimioterapia de Consolidação/economia , RecidivaRESUMO
Philadelphia-chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) is characterized by reciprocal chromosomal translocation between chromosome 9 and 22, leading to the expression of constitutively active oncogenic BCR-ABL1 fusion protein. CXC chemokine receptor 4 (CXCR4) is essential for the survival of BCR-ABL1-transformed mouse pre-B cells, as the deletion of CXCR4 induces death in these cells. To investigate whether CXCR4 inhibition also effectively blocks BCR-ABL1-transformed cell growth in vitro, in this study, we explored an array of peptide-based inhibitors of CXCR4. The inhibitors were optimized derivatives of EPI-X4, an endogenous peptide antagonist of CXCR4. We observed that among all the candidates, EPI-X4 JM#170 (referred to as JM#170) effectively induced cell death in BCR-ABL1-transformed mouse B cells but had little effect on untransformed wild-type B cells. Importantly, AMD3100, a small molecule inhibitor of CXCR4, did not show this effect. Treatment with JM#170 induced transient JNK phosphorylation in BCR-ABL1-transformed cells, which in turn activated the intrinsic apoptotic pathway by inducing cJun, Bim, and Bax gene expressions. Combinatorial treatment of JM#170 with ABL1 kinase inhibitor Imatinib exerted a stronger killing effect on BCR-ABL1-transformed cells even at a lower dose of Imatinib. Surprisingly, JM#170 actively killed Sup-B15 cells, a BCR-ABL1+ human ALL cell line, but had no effect on the BCR-ABL1- 697 cell line. This suggests that the inhibitory effect of JM#170 is specific for BCR-ABL1+ ALL. Taken together, JM#170 emerges as a potent novel drug against Ph+ ALL.
Assuntos
Proteínas de Fusão bcr-abl , Receptores CXCR4 , Receptores CXCR4/metabolismo , Receptores CXCR4/antagonistas & inibidores , Receptores CXCR4/genética , Proteínas de Fusão bcr-abl/genética , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Proteínas de Fusão bcr-abl/metabolismo , Animais , Camundongos , Humanos , Peptídeos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Linhagem Celular Tumoral , Cromossomo Filadélfia/efeitos dos fármacos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologiaRESUMO
Globally, Campylobacter spp. are responsible for most cases of bacterial gastrointestinal infections in humans and although rare, extraintestinal Campylobacter infections have been described. A 2-yearold neutropenic girl with underlying precursor B-cell acute lymphoblastic leukemia presented with a 3-day history of diarrhea. Her stool culture yielded no enteric bacterial pathogens. However, when her blood culture was flagged as positive for bacterial growth, no colonies could be observed on routine bacteriological isolation media. Nonetheless, gram-negative bacilli with seagull and spiral morphologies were seen when the surface of the isolation media used to subculture her blood was Gram-stained. Bacterial colonies were only visible when a subculture was attempted on a Campylobacter blood-free selective agar medium. The organism was identified as Campylobacter jejuni by matrix-assisted laser desorption ionization-time of flight mass spectrometry. Since the organism was erythromycin-resistant and the patient's age precluded the use of tetracycline and ciprofloxacin, an antibiotic regimen consisting of piperacillin-tazobactam and gentamicin was commenced. Her C. jejuni bacteremia resolved following eight days of antibiotic therapy.
Assuntos
Antibacterianos , Bacteriemia , Infecções por Campylobacter , Campylobacter jejuni , Humanos , Feminino , Bacteriemia/microbiologia , Bacteriemia/tratamento farmacológico , Bacteriemia/diagnóstico , Campylobacter jejuni/isolamento & purificação , Infecções por Campylobacter/tratamento farmacológico , Infecções por Campylobacter/microbiologia , Infecções por Campylobacter/diagnóstico , Antibacterianos/uso terapêutico , Pré-Escolar , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológicoRESUMO
AIMS: Acute lymphoblastic leukemia (ALL) is the most common type of pediatrics cancer. Chemokines exert different roles in leukemia process through leukocyte recruitment and regulation of disease severity. Due to the prominent roles of chemokine/receptor axes, this study aimed to measure the blood expression levels of CCR4 and their ligands in pediatrics with B-cell ALL (B-ALL). We also evaluated the impact of cytotoxic chemotherapy on this axis. MATERIAL AND METHOD: Thirty children suffering from B-ALL were included in the study and followed up for 30 days after completion of a chemotherapy course. The blood sampling was performed before and after chemotherapy. 30 healthy donors have also entered the study as control subjects. The mRNA expression of CCL17, CCL22 and CCR4 genes was determined by quantitative real-time PCR. The frequency of the peripheral blood mononuclear cells expressing CCR4 (CCR4 + PBMCs) was also evaluated by the flow cytometry method. Moreover, we evaluated the association of the CCL17/CCL22-CCR4 axis with some diagnostic, prognostic and predictive biomarkers in ALL patients. RESULTS: There was overexpression of the CCL17/CCL22-CCR4 axis along with lactate dehydrogenase (LDH) in pediatrics with B-ALL compared to healthy controls. After induction of chemotherapy, the blood expression levels of the CCL17/CCL22-CCR4 axis have reached the levels of healthy controls. The findings for the blood expression levels of CCR4 were also confirmed using flow cytometry. CONCLUSION: The CCL17/CCL22-CCR4 axis can be used as a novel predictive and prognostic biomarker in B-ALL.
Assuntos
Quimiocina CCL17 , Quimiocina CCL22 , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Receptores CCR4 , Humanos , Receptores CCR4/metabolismo , Receptores CCR4/genética , Quimiocina CCL22/genética , Quimiocina CCL22/metabolismo , Criança , Masculino , Quimiocina CCL17/genética , Quimiocina CCL17/sangue , Quimiocina CCL17/metabolismo , Feminino , Pré-Escolar , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/sangue , Leucócitos Mononucleares/metabolismo , Adolescente , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , PrognósticoRESUMO
Pro-B- and pre-B-cells are consecutive entities in early B-cell development, representing cells of origin for B-cell precursor acute lymphoid leukemia (BCP-ALL). Normal B-cell differentiation is critically regulated by specific transcription factors (TFs). Accordingly, TF-encoding genes are frequently deregulated or mutated in BCP-ALL. Recently, we described TF-codes which delineate physiological activities of selected groups of TF-encoding genes in hematopoiesis including B-cell development. Here, we exploited these codes to uncover regulatory connections between particular TFs in pro-B- and pre-B-cells via an analysis of developmental TFs encoded by NKL and TALE homeobox genes and by ETS and T-box genes. Comprehensive expression analyses in BCP-ALL cell lines helped identify validated models to study their mutual regulation in vitro. Knockdown and overexpression experiments and subsequent RNA quantification of TF-encoding genes in selected model cell lines revealed activating, inhibitory or absent connections between nine TFs operating in early B-cell development, including HLX, MSX1, IRX1, MEIS1, ETS2, ERG, SPIB, EOMES, and TBX21. In addition, genomic profiling revealed BCP-ALL subtype-specific copy number alterations of ERG at 21q22, while a deletion of the TGFbeta-receptor gene TGFBR2 at 3p24 resulted in an upregulation of EOMES. Finally, we combined the data to uncover gene regulatory networks which control normal differentiation of early B-cells, collectively endorsing more detailed evaluation of BCP-ALL subtypes.
Assuntos
Diferenciação Celular , Redes Reguladoras de Genes , Células Precursoras de Linfócitos B , Fatores de Transcrição , Humanos , Diferenciação Celular/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Células Precursoras de Linfócitos B/metabolismo , Células Precursoras de Linfócitos B/patologia , Linhagem Celular Tumoral , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Regulação Leucêmica da Expressão GênicaAssuntos
Anticorpos Biespecíficos , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Indução de Remissão , Humanos , Anticorpos Biespecíficos/uso terapêutico , Anticorpos Biespecíficos/efeitos adversos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Feminino , Adulto , Pessoa de Meia-Idade , Transplante de Células-Tronco Hematopoéticas , Adolescente , Adulto Jovem , Antineoplásicos/uso terapêuticoRESUMO
BACKGROUND: Precursor B-cell acute lymphoblastic leukemia (B-ALL) is the most common cancers in children. Failure of induction chemotherapy is a major factor leading to relapse and death in children with B-ALL. Given the importance of altered metabolites in the carcinogenesis of pediatric B-ALL, studying the metabolic profile of children with B-ALL during induction chemotherapy and in different minimal residual disease (MRD) status may contribute to the management of pediatric B-ALL. METHODS: We collected paired peripheral blood plasma samples from children with B-ALL at pre- and post-induction chemotherapy and analyzed the metabolomic profiling of these samples by ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS). Healthy children were included as controls. We selected metabolites that were depleted in pediatric B-ALL and analyzed the concentrations in pediatric B-ALL samples. In vitro, we study the effects of the selected metabolites on the viability of ALL cell lines and the sensitivity to conventional chemotherapeutic agents in ALL cell lines. RESULTS: Forty-four metabolites were identified with different levels between groups. KEGG pathway enrichment analyses revealed that dysregulated linoleic acid (LA) metabolism and arginine (Arg) biosynthesis were closely associated with pediatric B-ALL. We confirmed that LA and Arg were decreased in pediatric B-ALL samples. The treatment of LA and Arg inhibited the viability of NALM-6 and RS4;11 cells in a dose-dependent manner, respectively. Moreover, Arg increased the sensitivity of B-ALL cells to L-asparaginase and daunorubicin. CONCLUSION: Arginine increases the sensitivity of B-ALL cells to the conventional chemotherapeutic drugs L-asparaginase and daunorubicin. This may represent a promising therapeutic approach.
Assuntos
Arginina , Metabolômica , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/sangue , Arginina/metabolismo , Arginina/sangue , Criança , Feminino , Metabolômica/métodos , Pré-Escolar , Masculino , Estudos de Casos e Controles , Neoplasia Residual , Cromatografia Líquida de Alta Pressão , Linhagem Celular Tumoral , Metaboloma , Quimioterapia de Indução , Adolescente , LactenteRESUMO
INTRODUCTION: Chimeric antigen receptor (CAR) T-cells have revolutionized cancer treatment, showing significant success, including treatment of pediatric B-cell acute lymphoblastic leukemia (B-ALL). Despite their efficacy, cytokine release syndrome (CRS) emerges as a common early adverse effect that can be life threatening in severe cases, resulting from the immune system's targeted activation against tumors. AREAS COVERED: This review concentrates on CRS in children and young adults undergoing CAR T-cell therapy for B-ALL. It explores CRS pathophysiology, clinical presentation, and incidence, emphasizing the importance of a consensus definition and grading to homogenize the treatment according to the severity of symptoms. We will discuss the standard of care treatment of CRS but also novel approaches. We will highlight the importance of managing CRS without compromising the efficacy of immune cell activation against tumors. EXPERT OPINION: As CAR T-cell therapy in pediatric B-ALL become increasingly available and used, optimal management of CRS becomes increasingly important. Early recognition and timely management has improved. Further information will aid us to identify optimal timing of tocilizumab and corticosteroids. Continued bench research coupled with clinical studies and biomarker discovery will allow for valuable insights into CRS pathophysiology and patient and/or cell-targeted treatments.
Assuntos
Síndrome da Liberação de Citocina , Imunoterapia Adotiva , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Humanos , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/terapia , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Criança , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/imunologia , Adolescente , Receptores de Antígenos Quiméricos/imunologia , Índice de Gravidade de DoençaRESUMO
OBJECTIVE: We aimed to evaluate the efficacy of decitabine consolidation after treatment with CD19/CD22 chimeric antigen receptor T-cell (CAR-T) for patients with relapsed/refractory B-cell acute lymphoblastic leukaemia (r/r B-ALL). METHODS: We retrospectively analysed 48 patients with r/r B-ALL who received CD19/CD22 CAR-T therapy between September 2017 and May 2021. Sixteen patients received decitabine consolidation (20â¯mg/m2/day for 5 days at 3-month intervals) after CAR-T therapy (DAC group), while 32 patients did not receive decitabine consolidation (CON group). Overall survival (OS), leukaemia-free survival (LFS), and cumulative incidence of relapse (CIR) were evaluated in both groups. Time-to-event analysis was performed using the Kaplan-Meier method. RESULTS: The median follow-up periods in the DAC and CON groups were 41.2 months and 28.6 months, respectively. The 4-year OS and 4-year LFS rates in both groups were 93.3â¯% and 64.3â¯% (P=0.029) and 87.5â¯% and 55.9â¯% (P=0.059), respectively. The 1-year CIR was 6.25â¯% and 28.6â¯%, respectively. Univariate and multivariate Cox regression analyses showed that decitabine consolidation after CAR-T therapy was significantly associated with superior OS (hazard ratio [HR]: 0.121, 95â¯% confidence interval [CI]: 0.015-0.947, P=0.044), and bridging to haematopoietic stem cell transplantation after CAR-T therapy was significantly associated with superior LFS (HR: 0.279, 95â¯%CI: 0.093-0.840, P=0.023). CONCLUSIONS: Our study recommends decitabine consolidation after CD19/CD22 CAR-T therapy as a novel maintenance strategy to improve the survival outcomes of patients with r/r B-ALL.
Assuntos
Antígenos CD19 , Decitabina , Imunoterapia Adotiva , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico , Humanos , Decitabina/uso terapêutico , Decitabina/administração & dosagem , Feminino , Masculino , Imunoterapia Adotiva/métodos , Adulto , Estudos Retrospectivos , Pessoa de Meia-Idade , Adolescente , Antígenos CD19/imunologia , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/imunologia , Adulto Jovem , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Antimetabólitos Antineoplásicos/uso terapêutico , Taxa de Sobrevida , Quimioterapia de Consolidação , Seguimentos , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/terapia , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Receptores de Antígenos Quiméricos/imunologia , Criança , Quimioterapia de Manutenção , IdosoAssuntos
Anticorpos Biespecíficos , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Humanos , Anticorpos Biespecíficos/uso terapêutico , Neoplasia Residual/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Adulto , Resultado do Tratamento , Antineoplásicos/uso terapêuticoRESUMO
BACKGROUND: The predictive importance of IKZF1del in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) has shown variability across different studies. Thus, the optimal treatment approach for children with IKZF1del BCP-ALL remains contentious, with the ongoing debate surrounding the use of IKZF1del-based high-risk stratification versus a minimal residual disease (MRD)-guided protocol. METHODS: IKZF1 status was reliably determined in 804 patients using multiplex ligation-dependent probe amplification (MLPA) data obtained from four hospitals in Fujian, a province of China. In the Chinese Children Leukemia Group (CCLG)-ALL 2008 cohort, IKZF1 status was included in the risk assignment, with all IKZF1del patients receiving a high-risk regimen. Conversely, in the Chinese Children's Cancer Group (CCCG)-ALL 2015 cohort, IKZF1del was not incorporated into the risk assignment, and patients were treated based on an MRD-guided risk stratification protocol. RESULTS: IKZF1del was found in 86 patients (86/804, 10.7%) overall and in 30 (30/46, 65.2%) BCR::ABL1-positive patients. Overall, IKZF1del was a poor prognostic predictor for patients, though the significance diminished upon age adjustment, white blood cell (WBC) count at diagnosis, treatment group, and MRD status. In the CCLG-ALL 2008 cohort, IKZF1del conferred a notably lower 5-year overall survival (OS) and event-free survival (EFS) and a significantly higher 5-year cumulative incidence of relapse (CIR) than IKZF1wt. In the CCLG-ALL 2015 cohort, IKZF1del conferred a lower 5-year OS and EFS and a higher 5-year CIR than IKZF1wt, but the differences were insignificant. The IKZF1del patients treated with higher intensity chemotherapy (CCLG-ALL 2008 high-risk regimen) had a markedly lower 5-year OS and EFS compared with those treated with the MRD-guided protocol (CCCG-ALL 2015 protocol). Furthermore, patients treated with the CCLG-ALL 2008 high-risk regimen experienced a higher frequency of serious adverse events (SAEs), especially infection-related SAEs, compared with those treated with the CCCG-ALL 2015 MRD-guided protocol. CONCLUSIONS: The prognostic effect of IKZF1del may vary in different protocols. Compared with higher intensity chemotherapy, the MRD-guided protocol may be a more effective approach to treating BCP-ALL with IKZF1del in children.
Assuntos
Fator de Transcrição Ikaros , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Humanos , Fator de Transcrição Ikaros/genética , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Feminino , Criança , Prognóstico , Pré-Escolar , Neoplasia Residual/genética , Lactente , Adolescente , China/epidemiologia , Deleção de GenesRESUMO
Precision oncology promises individually tailored drugs and clinical care for patients with cancer: That is, "the right drug, for the right patient, at the right dose, and at the right time." Although stratification of the risk for treatment resistance and toxicity is key to precision oncology, there are multiple ways in which such stratification can be achieved, for example, genetic, functional pathway based, among others. Moving toward precision oncology is sorely needed in the case of acute lymphoblastic leukemia (ALL) wherein adult patients display survival rates ranging from 30% to 70%. The present study reports on the pathway activity signature of adult B-ALL, with an eye to precision oncology. Transcriptome profiles from three different expression datasets, comprising 346 patients who were adolescents or adults with B-ALL, were harnessed to determine the activity of signaling pathways commonly disrupted in B-ALL. Pathway activity analyses revealed that Ph-like ALL closely resembles Ph-positive ALL. Although this was the case at the average pathway activity level, the pathway activity patterns in B-ALL differ from genetic subtypes. Importantly, clustering analysis revealed that five distinct clusters exist in B-ALL patients based on pathway activity, with each cluster displaying a unique pattern of pathway activation. Identifying pathway-based subtypes thus appears to be crucial, considering the inherent heterogeneity among patients with the same genetic subtype. In conclusion, a pathway-based stratification of the B-ALL could potentially allow for simultaneously targeting highly active pathways within each ALL subtype, and thus might open up new avenues of innovation for personalized/precision medicine in this cancer that continues to have poor prognosis in adult patients compared with the children.
Assuntos
Medicina de Precisão , Humanos , Medicina de Precisão/métodos , Adulto , Transdução de Sinais/genética , Perfilação da Expressão Gênica/métodos , Transcriptoma , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Adolescente , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Feminino , Prognóstico , Análise por ConglomeradosRESUMO
ABSTRACT: A chemoport is widely used in paediatric oncology population. Removal is a relatively easy procedure, but difficulty can be encountered in case the catheter is densely adherent to the vascular wall. It is a rare complication and is associated with long indwelling duration and acute lymphoblastic leukaemia (ALL). Forceful traction can lead to vascular injury and high morbidity. Herein, we report a 7-year-old girl with precursor B ALL who had delayed chemoport removal due to the coronavirus disease (COVID-19) pandemic. The removal process was difficult, as the catheter was adherent to the right innominate vein. Out of panic, the surgeon pulled it out forcefully. Fortunately, the catheter and its fragment were successfully retrieved completely and the child was discharged the next day. The management strategy varies and ranges from minimally invasive to open surgery. Leaving a stuck chemoport catheter in situ can be a bailout method or part of conservative management.