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Romanian Journal of Internal Medicine =... 2015Acute lymphoblastic leukemia (ALL) is a malignant neoplasm of the lymphocyte precursor cells. Among adults it is a relatively rare neoplasm with a curability rate around... (Review)
Review
Acute lymphoblastic leukemia (ALL) is a malignant neoplasm of the lymphocyte precursor cells. Among adults it is a relatively rare neoplasm with a curability rate around 30% at 5 years. Currently, the diagnosis and classification of ALL is a multistep procedure that relies on the simultaneous application of multiple techniques that include: cytomorphology, immunophenotype and cytogenetic assays. Some of them have important clinical implications for both diagnosis and predicting response to specific treatment regimens, while the role of others is still to be defined. Over the years, several prognostic factors have been identified and today a risk stratification at diagnosis and during the follow-up is based on the characteristics of the leukemic cells.
Topics: Adult; Humans; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis
PubMed: 26076558
DOI: 10.1515/rjim-2015-0004 -
BMC Cancer Dec 2022To evaluate the prognostic factors and outcome for acute lymphoblastic leukemia (ALL) in children with MLL rearrangement (MLL-r).
PURPOSE
To evaluate the prognostic factors and outcome for acute lymphoblastic leukemia (ALL) in children with MLL rearrangement (MLL-r).
METHODS
A total of 124 pediatric patients who were diagnosed with ALL were classified into two groups based on the MLL-r status by using a retrospective case-control study method from June 2008 to June 2020.
RESULTS
The prevalence of MLL-r positive in the whole cohort was 4.9%. The complete remission (CR) rate on Day 33 in the MLL-r positive group was not statistically different from the negative group (96.8% vs 97.8%, P = 0.736). Multivariate analysis showed that T-cell, white blood cell counts (WBC) ≥ 50 × 10/L, MLL-AF4, and D15 minimal residual disease (MRD) positive were independent risk factors affecting the prognosis of MLL-r positive children. Stem cell transplantation (SCT) was a favorable independent prognostic factor affecting event-free survival (EFS) in MLL-r positive patients (P = 0.027), and there was a trend toward an independent prognostic effect on overall survival (OS) (P = 0.065). The 10-year predicted EFS for patients with MLL-AF4, MLL-PTD, MLL-ENL, other MLL partner genes, and MLL-r negative cases were 46.67 ± 28.61%, 85.71 ± 22.37%, 75 ± 32.41%, 75 ± 32.41%, and 77.33 ± 10.81%, respectively (P = 0.048). The 10-year predicted OS were 46.67 ± 28.61%, 85.71 ± 22.37%, 75 ± 32.41%, 75 ± 32.41%, and 85.2 ± 9.77%, respectively (P = 0.049). The 124 patients with ALL were followed up and eventually 5 (4%) cases relapsed, with a median relapse time of 3.9 years.
CONCLUSION
Patients with MLL-r positive ALL have moderate remission rates, but are prone to relapse with low overall survival. The outcome of MLL-r positive ALL was closely related to the partner genes, and clinical attention should be paid to screening for MLL partner genes and combining them with other prognostic factors for accurate risk stratification.
Topics: Humans; Child; Case-Control Studies; Prognosis; Retrospective Studies; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Chromosome Aberrations; Recurrence
PubMed: 36461002
DOI: 10.1186/s12885-022-10378-w -
Cancer Epidemiology Jun 2020The association of population mixing (PM) with childhood acute lymphocytic leukemia (ALL) has been reproduced in multiple studies. However, the mechanism underlying this...
BACKGROUND
The association of population mixing (PM) with childhood acute lymphocytic leukemia (ALL) has been reproduced in multiple studies. However, the mechanism underlying this association is unknown.
METHODS
Ecological study of incidence of pediatric ALL among 253 counties in the State of Texas (USA) using surrogates of genetic and environmental PM. ALL incidence data were obtained from Texas Cancer Registry and county population statistics from the US Census Bureau. Poisson regression was used to compare ALL incidence and PM.
RESULTS
There is substantial and variable genetic and environmental PM among counties in Texas. Indicators of genetic PM including proportion of multiracial households, ratio of Hispanics to non-Hispanics, and ratio of foreign to native-born residents were all significantly associated with a higher incidence of ALL (IRR 1.81 (95CI 1.05-3.13), 1.67 (95CI 1.16-2.37), and 1.59 (95CI 1.03-2.48), respectively). Surrogates of environmental PM namely population density and persons per household were not associated with incidence of ALL; IRRs 1.29 (95CI 0.4-4.15) and 1.47 (95CI 0.89-2.43).
CONCLUSIONS
These findings are consistent with prior patterns and magnitudes of PM association with ALL. Our findings suggest that the implicated mechanism of leukemogenesis in PM may be genetically transmitted rather than environmental.
Topics: Child; Female; Humans; Incidence; Infant; Male; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Young Adult
PubMed: 32353774
DOI: 10.1016/j.canep.2020.101722 -
International Braz J Urol : Official... 2022
Topics: Child; Humans; Male; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Testicular Neoplasms
PubMed: 36037260
DOI: 10.1590/S1677-5538.IBJU.2022.0318 -
American Society of Clinical Oncology... 2013The treatment of young adults (16 to 39 years of age) with acute lymphocytic leukemia (ALL) has been a focus of clinical research over the past decade. This review will... (Review)
Review
The treatment of young adults (16 to 39 years of age) with acute lymphocytic leukemia (ALL) has been a focus of clinical research over the past decade. This review will focus on the biology, optimal treatment, treatment-related toxicities, and psychosocial issues in this patient population.
Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Chromosome Aberrations; Gene Expression Regulation, Leukemic; Hematopoietic Stem Cell Transplantation; Humans; Patient Compliance; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Transplantation, Homologous; Young Adult
PubMed: 23714524
DOI: 10.14694/EdBook_AM.2013.33.285 -
Annals of Hematology Sep 2023The objective of this study is to explore the clinical features and outcomes of pediatric patients with acute lymphoblastic leukemia (ALL) harboring JAK-STAT signaling...
The objective of this study is to explore the clinical features and outcomes of pediatric patients with acute lymphoblastic leukemia (ALL) harboring JAK-STAT signaling pathway genetic abnormalities. This retrospective case series examined the clinical data of pediatric patients diagnosed with ALL harboring JAK-STAT pathway genetic abnormality at the Children's Hospital of the Capital Institute of Pediatrics between January 2016 and January 2022. Bone marrow next-generation sequencing was used to reveal the JAK pathway abnormalities. Descriptive statistics were used. From 432 children with ALL during the study period, eight had JAK-STAT pathway genetic abnormalities. Regarding immunotyping, there were four patients with common-B cell types and one with pre-B cell type. The three patients with T-ALL had early T-cell precursor(ETP) type, pre-T cell type, and T cell type. Gene mutations were more common than fusion genes. There was no central nervous system involvement in eight patients. All patients were considered at least at intermediate risk before treatments. Four patients underwent hematopoietic stem cell transplantation (HSCT). One child had a comprehensive relapse and died. The child had a severe infection and could not tolerate high-intensity chemotherapy. Another child relapsed 2 years after HSCT and died. Disease-free survival was achieved in six children. JAK-STAT pathway genetic abnormalities in pediatric Ph-like ALL are rare. Special attention should be paid to treatment-related complications, such as infection and combination therapy (chemotherapy, small molecule targeted drugs, immunotherapy, etc.) to reduce treatment-related death and improve long-term quality of life.
Topics: Humans; Child; Janus Kinases; Retrospective Studies; Quality of Life; Signal Transduction; STAT Transcription Factors; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Hematopoietic Stem Cell Transplantation
PubMed: 37209119
DOI: 10.1007/s00277-023-05245-y -
Blood Jul 2022In October 2021, brexucabtagene autoleucel became the first anti-CD19 chimeric antigen receptor T-cell product to receive approval from the Food and Drug Administration... (Review)
Review
In October 2021, brexucabtagene autoleucel became the first anti-CD19 chimeric antigen receptor T-cell product to receive approval from the Food and Drug Administration to treat adults with relapsed and refractory B-cell acute lymphoblastic leukemia. The approval is based on results from the Zuma-3 trial and significantly widens treatment options for this patient population. In this article, we review outcomes from this study and its implications.
Topics: Acute Disease; Adult; Antigens, CD19; Humans; Immunotherapy, Adoptive; Lymphoma, B-Cell; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Receptors, Antigen, T-Cell; Receptors, Chimeric Antigen
PubMed: 35507688
DOI: 10.1182/blood.2021014892 -
The Lancet. Haematology Oct 2021CNS relapse of acute lymphocytic leukaemia is difficult to treat. Durable remissions of relapsed or refractory B-cell acute lymphocytic leukaemia have been observed... (Clinical Trial)
Clinical Trial
CD19-targeted chimeric antigen receptor T-cell therapy for CNS relapsed or refractory acute lymphocytic leukaemia: a post-hoc analysis of pooled data from five clinical trials.
BACKGROUND
CNS relapse of acute lymphocytic leukaemia is difficult to treat. Durable remissions of relapsed or refractory B-cell acute lymphocytic leukaemia have been observed following treatment with CD19-directed chimeric antigen receptor (CAR) T cells; however, most trials have excluded patients with active CNS disease. We aimed to assess the safety and activity of CAR T-cell therapy in patients with a history of CNS relapsed or refractory B-cell acute lymphocytic leukaemia.
METHODS
In this post-hoc analysis, we included 195 patients (aged 1-29 years; 110 [56%] male and 85 [44%] female) with relapsed or refractory CD19-positive acute lymphocytic leukaemia or lymphocytic lymphoma from five clinical trials (Pedi CART19, 13BT022, ENSIGN, ELIANA, and 16CT022) done at the Children's Hospital of Philadelphia (Philadelphia, PA, USA), in which participants received CD19-directed CAR T-cell therapy between April 17, 2012, and April 16, 2019. The trials required control of CNS disease at enrolment and infusion and excluded treatment in the setting of acute neurological toxic effects (>grade 1 in severity) or parenchymal lesions deemed to increase the risk of neurotoxicity. 154 patients from Pedi CART19, ELIANA, ENSIGN, and 16CT022 received tisagenlecleucel and 41 patients from the 13BT022 trial received the humanised CD19-directed CAR, huCART19. We categorised patients into two strata on the basis of CNS status at relapse or within the 12 months preceding CAR T-cell infusion-either CNS-positive or CNS-negative disease. Patients with CNS-positive disease were further divided on the basis of morphological bone marrow involvement-either combined bone marrow and CNS involvement, or isolated CNS involvement. Endpoints were the proportion of patients with complete response at 28 days after infusion, Kaplan-Meier analysis of relapse-free survival and overall survival, and the incidence of cytokine release syndrome and neurotoxicity.
FINDINGS
Of all 195 patients, 66 (34%) were categorised as having CNS-positive disease and 129 (66%) as having CNS-negative disease, and 43 (22%) were categorised as having isolated CNS involvement. The median length of follow-up was 39 months (IQR 25-49) in the CNS-positive stratum and 36 months (18-49) in the CNS-negative stratum. The proportion of patients in the CNS-positive stratum with a complete response at 28 days after infusion was similar to that in the CNS-negative stratum (64 [97%] of 66 vs 121 [94%] of 129; p=0·74), with no significant difference in relapse-free survival (60% [95% CI 49-74] vs 60% [51-71]; p=0·50) or overall survival (83% [75-93] vs 71% [64-79]; p=0·39) at 2 years between the two groups. Overall survival at 2 years was significantly higher in patients with isolated CNS involvement compared with those with bone marrow involvement (91% [82-100] vs 71% [64-78]; p=0·046). The incidence and severity of neurotoxicity (any grade, 53 [41%] vs 38 [58%]; grade 1, 24 [19%] vs 20 [30%]; grade 2, 14 [11%] vs 10 [15%]; grade 3, 12 [9%] vs 6 [9%], and grade 4, 3 [2%] vs 2 [3%]; p=0·20) and cytokine release syndrome (any grade, 110 [85%] vs 53 [80%]; grade 1, 12 [9%] vs 2 [3%]; grade 2, 61 [47%] vs 38 [58%]; grade 3, 18 [14%] vs 7 [11%] and grade 4, 19 [15%] vs 6 [9%]; p=0·26) did not differ between the CNS-negative and the CNS-positive disease strata.
INTERPRETATION
Tisagenlecleucel and huCART19 are active at clearing CNS disease and maintaining durable remissions in children and young adults with CNS relapsed or refractory B-cell acute lymphocytic leukaemia or lymphocytic lymphoma, without increasing the risk of severe neurotoxicity; although care should be taken in the timing of therapy and disease control to mitigate this risk. These preliminary findings support the use of these CAR T-cell therapies for patients with CNS relapsed or refractory B-cell acute lymphocytic leukaemia.
FUNDING
Children's Hospital of Philadelphia Frontier Program.
Topics: Adolescent; Adult; Antigens, CD19; Central Nervous System Neoplasms; Child, Preschool; Female; Humans; Immunotherapy, Adoptive; Infant; Male; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Receptors, Chimeric Antigen; Recurrence; Young Adult
PubMed: 34560014
DOI: 10.1016/S2352-3026(21)00238-6 -
Current Hematologic Malignancy Reports Jun 2012During the last decade a tremendous technologic progress based on genome-wide profiling of genetic aberrations, structural DNA alterations, and sequence variations has... (Review)
Review
During the last decade a tremendous technologic progress based on genome-wide profiling of genetic aberrations, structural DNA alterations, and sequence variations has allowed a better understanding of the molecular basis of pediatric and adult B/T-acute lymphoblastic leukemia (ALL), contributing to a better recognition of the biological heterogeneity of ALL and to a more precise definition of risk factors. Importantly, these advances identified novel potential targets for therapeutic intervention. This review will be focused on the cytogenetic/molecular advances in pediatric and adult ALL based on recently published articles.
Topics: Cytogenetic Analysis; Gene Expression Profiling; Genome, Human; Humans; Mutation; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Sequence Analysis, DNA
PubMed: 22528731
DOI: 10.1007/s11899-012-0122-5 -
BMC Cancer Feb 2023Precursor B-cell acute lymphoblastic leukemia (pre-B ALL) is the most common hematological malignancy in children. Cellular metabolic reorganization is closely related...
BACKGROUND
Precursor B-cell acute lymphoblastic leukemia (pre-B ALL) is the most common hematological malignancy in children. Cellular metabolic reorganization is closely related to the progression and treatment of leukemia. We found that the level of 1,5-anhydroglucitol (1,5-AG), which is structurally similar to glucose, was elevated in children with pre-B ALL. However, the effect of 1,5-AG on pre-B ALL was unclear. Here, we aimed to reveal the roles and mechanisms of 1,5-AG in pre-B ALL progression.
METHODS
The peripheral blood plasma level of children with initial diagnosis of pre-B ALL and that of healthy children was measured using untargeted metabolomic analysis. Cell Counting Kit-8 assay, RNA sequencing, siRNA transfection, real-time quantitative PCR, and western blot were performed using pre-B ALL cell lines Reh and HAL-01. Cell cycle, cell apoptosis, ROS levels, and the positivity rate of CD19 were assessed using flow cytometry. Oxygen consumption rates and extracellular acidification rate were measured using XFe24 Extracellular Flux Analyzer. The lactate and nicotinamide adenine dinucleotide phosphate levels were measured using kits. The effect of 1,5-AG on pre-B ALL progression was verified using the In Vivo Imaging System in a xenotransplantation leukemia model.
RESULTS
We confirmed that 1,5-AG promoted the proliferation, viability, and intracellular glycolysis of pre-B ALL cells. Mechanistically, 1,5-AG promotes glycolysis while inhibiting mitochondrial respiration by upregulating pyruvate dehydrogenase kinase 4 (PDK4). Furthermore, high levels of intracellular glycolysis promote pre-B ALL progression by activating the reactive oxygen species (ROS)-dependent mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway. Conversely, N-acetylcysteine or vitamin C, an antioxidant, effectively inhibited 1,5-AG-mediated progression of leukemia cells.
CONCLUSIONS
Our study reveals a previously undiscovered role of 1,5-AG in pre-B ALL, which contributes to an in-depth understanding of anaerobic glycolysis in the progression of pre-B ALL and provides new targets for the clinical treatment of pre-B ALL.
Topics: Child; Humans; Reactive Oxygen Species; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Glycolysis; Extracellular Signal-Regulated MAP Kinases; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Apoptosis; Cell Proliferation; Cell Line, Tumor
PubMed: 36747147
DOI: 10.1186/s12885-023-10589-9