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Hematology. American Society of... Nov 2018Acute lymphoblastic leukemia (ALL) is characterized by genetic alterations that block differentiation, promote proliferation of lymphoid precursor cells, and are... (Review)
Review
Acute lymphoblastic leukemia (ALL) is characterized by genetic alterations that block differentiation, promote proliferation of lymphoid precursor cells, and are important for risk stratification. Although ALL is less common in adolescents and young adults (AYAs) and adults than children, survival rates are inferior, and long-term prognosis for adults is poor. Thus, ALL remains a challenging disease to treat in the AYA and adult populations. A major contributing factor that influences prognosis in this population is the reduced prevalence of genetic subtypes associated with favorable outcome and a concomitant increase in subtypes associated with poor outcome. Recent advances in genomic profiling across the age spectrum continue to enhance our knowledge of the differences in disease biology between children and adults and are providing important insights into novel therapeutic targets. Philadelphia chromosome-like (Ph-like) ALL is one such subtype characterized by alterations that deregulate cytokine receptor or tyrosine kinase signaling and are amenable to inhibition with approved tyrosine kinase inhibitors. One of the greatest challenges now remaining is determining how to implement this breadth of genomic information into rapid and accurate diagnostic testing to facilitate the development of novel clinical trials that improve the outcome of AYAs and adults with ALL.
Topics: Adolescent; Adult; Child; Child, Preschool; Female; Humans; Infant; Male; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis
PubMed: 30504302
DOI: 10.1182/asheducation-2018.1.137 -
Cancer Imaging : the Official... Feb 2013Acute leukaemias are relatively common malignancies. Treatment has advanced significantly in the recent past and there has been improved patient survival. This improved... (Review)
Review
Acute leukaemias are relatively common malignancies. Treatment has advanced significantly in the recent past and there has been improved patient survival. This improved initial response is leading to an increasing number of cases of relapse. Extramedullary relapse occurs in a wide variety of locations with varying presentations, imaging findings and differentials. The pathophysiology and clinical course of recurrent extramedullary myeloid and lymphocytic leukaemias are reviewed in this article. The wide variety of imaging findings associated with many important sites of recurrence and the associated differential diagnosis are discussed and illustrated.
Topics: Diagnosis, Differential; Female; Humans; Leukemia, Myeloid, Acute; Magnetic Resonance Imaging; Male; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Tomography, X-Ray Computed
PubMed: 23439108
DOI: 10.1102/1470-7330.2013.0004 -
Journal of Cancer Research and... 2021Selenium is obligatory for proper functioning of body as it is the part of enzyme protection system. Its both organic and inorganic forms are thought to be active as an...
Selenium is obligatory for proper functioning of body as it is the part of enzyme protection system. Its both organic and inorganic forms are thought to be active as an antitumor agent. We trialed the different dosages (0 × 10 M, 2.7 × 10 M, 5.4 × 10 M, and 8.1 × 10 M) of sodium selenite given to the acute lymphocytic leukemia cell lines incubated for 24, 48, and 72 h. The ratios of dead cells to live cells when treated with sodium selenite were very high as compared to the control with no treatment. This dosage-dependent apoptosis increased with the incubation time.
Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Humans; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Sodium Selenite; Trace Elements
PubMed: 33723167
DOI: 10.4103/jcrt.JCRT_147_17 -
Acta Haematologica 2013Although survival rates for acute lymphocytic leukemia (ALL), especially in children, have shown dramatic improvement over time, poor outcomes are still observed in... (Review)
Review
Although survival rates for acute lymphocytic leukemia (ALL), especially in children, have shown dramatic improvement over time, poor outcomes are still observed in patients who have refractory or relapsed disease after conventional chemotherapy. New therapeutic options are urgently needed. Bortezomib (Velcade, formerly PS-341) is the first proteasome inhibitor approved by the US FDA for the treatment of newly diagnosed multiple myeloma and relapsed/refractory multiple myeloma and mantle cell lymphoma. Although the mechanisms of bortezomib anticancer activity are still not completely understood, it is a new treatment option for patients with refractory or relapsed ALL, particularly when used in combination with conventional chemotherapy or targeted agents. This review summarizes recent advancements in the understanding of the bortezomib molecular mechanism of action in ALL. Understanding of the molecular approaches might help customize cancer chemotherapy for each individual patient, directing the field towards rational therapeutics.
Topics: Antineoplastic Agents; Boronic Acids; Bortezomib; Drug Therapy, Combination; Fusion Proteins, bcr-abl; Gastrointestinal Diseases; Humans; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Proteasome Endopeptidase Complex; Pyrazines; Signal Transduction; Thrombocytopenia; Valproic Acid
PubMed: 23295437
DOI: 10.1159/000345260 -
Blood Nov 2017Tisagenlecleucel (CTL019) is an investigational immunotherapy that involves reprogramming a patient's own T cells with a transgene encoding a chimeric antigen receptor...
Tisagenlecleucel (CTL019) is an investigational immunotherapy that involves reprogramming a patient's own T cells with a transgene encoding a chimeric antigen receptor to identify and eliminate CD19-expressing cells. We previously reported that CTL019 achieved impressive clinical efficacy in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL), including the expansion and persistence of CTL019 cells, which correlates with response to therapy. Here, we performed formal cellular kinetic analyses of CTL019 in a larger cohort of 103 patients treated with CTL019 in 2 different diseases (ALL and CLL). CTL019 was measured in peripheral blood and bone marrow, using quantitative polymerase chain reaction and flow cytometry. CTL019 levels in peripheral blood typically peaked at 10 to 14 days postinfusion and then declined slowly over time. Patients with complete response (CR)/CR with incomplete count recovery had higher levels of CTL019 in peripheral blood, with greater maximal concentration and area under the curve values compared with nonresponding patients ( < .0001 for each). CTL019 transgene levels were measurable up to 780 days in peripheral blood. CTL019 trafficking and persistence were observed in bone marrow and cerebrospinal fluid. CTL019 expansion correlated with severity of cytokine release syndrome (CRS) and preinfusion tumor burden in pediatric ALL. The results described here are the first detailed formal presentation of cellular kinetics across 2 diseases and highlight the importance of the application of in vivo cellular kinetic analyses to characterize clinical efficacy and CRS severity associated with CTL019 therapy.
Topics: Adolescent; Adult; Aged; Antibodies, Monoclonal, Humanized; Bone Marrow Cells; Cell Proliferation; Child; Child, Preschool; Cytokines; Humans; Infant; Kinetics; Leukemia, Lymphocytic, Chronic, B-Cell; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Receptors, Antigen, T-Cell; Recurrence; Transgenes; Tumor Burden; Young Adult
PubMed: 28935694
DOI: 10.1182/blood-2017-06-786129 -
BMC Cancer Jun 2020The clonoSEQ® Assay (Adaptive Biotechnologies Corporation, Seattle, USA) identifies and tracks unique disease-associated immunoglobulin (Ig) sequences by...
Analytical evaluation of the clonoSEQ Assay for establishing measurable (minimal) residual disease in acute lymphoblastic leukemia, chronic lymphocytic leukemia, and multiple myeloma.
BACKGROUND
The clonoSEQ® Assay (Adaptive Biotechnologies Corporation, Seattle, USA) identifies and tracks unique disease-associated immunoglobulin (Ig) sequences by next-generation sequencing of IgH, IgK, and IgL rearrangements and IgH-BCL1/2 translocations in malignant B cells. Here, we describe studies to validate the analytical performance of the assay using patient samples and cell lines.
METHODS
Sensitivity and specificity were established by defining the limit of detection (LoD), limit of quantitation (LoQ) and limit of blank (LoB) in genomic DNA (gDNA) from 66 patients with multiple myeloma (MM), acute lymphoblastic leukemia (ALL), or chronic lymphocytic leukemia (CLL), and three cell lines. Healthy donor gDNA was used as a diluent to contrive samples with specific DNA masses and malignant-cell frequencies. Precision was validated using a range of samples contrived from patient gDNA, healthy donor gDNA, and 9 cell lines to generate measurable residual disease (MRD) frequencies spanning clinically relevant thresholds. Linearity was determined using samples contrived from cell line gDNA spiked into healthy gDNA to generate 11 MRD frequencies for each DNA input, then confirmed using clinical samples. Quantitation accuracy was assessed by (1) comparing clonoSEQ and multiparametric flow cytometry (mpFC) measurements of ALL and MM cell lines diluted in healthy mononuclear cells, and (2) analyzing precision study data for bias between clonoSEQ MRD results in diluted gDNA and those expected from mpFC based on original, undiluted samples. Repeatability of nucleotide base calls was assessed via the assay's ability to recover malignant clonotype sequences across several replicates, process features, and MRD levels.
RESULTS
LoD and LoQ were estimated at 1.903 cells and 2.390 malignant cells, respectively. LoB was zero in healthy donor gDNA. Precision ranged from 18% CV (coefficient of variation) at higher DNA inputs to 68% CV near the LoD. Variance component analysis showed MRD results were robust, with expected laboratory process variations contributing ≤3% CV. Linearity and accuracy were demonstrated for each disease across orders of magnitude of clonal frequencies. Nucleotide sequence error rates were extremely low.
CONCLUSIONS
These studies validate the analytical performance of the clonoSEQ Assay and demonstrate its potential as a highly sensitive diagnostic tool for selected lymphoid malignancies.
Topics: Bone Marrow; Cyclin D1; Gene Rearrangement; High-Throughput Nucleotide Sequencing; Humans; Immunoglobulin Heavy Chains; Immunoglobulin lambda-Chains; Immunoglobulins; Leukemia, Lymphocytic, Chronic, B-Cell; Limit of Detection; Multiple Myeloma; Neoplasm, Residual; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Proto-Oncogene Proteins c-bcl-2; Reagent Kits, Diagnostic; Translocation, Genetic
PubMed: 32605647
DOI: 10.1186/s12885-020-07077-9 -
Seminars in Hematology Jan 2009
Topics: Age Factors; Humans; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 19100362
DOI: 10.1053/j.seminhematol.2008.09.011 -
The Oncologist Jul 2016: Acute lymphoblastic leukemia (ALL) is a heterogeneous group of hematologic malignancies that arise from clonal proliferation of immature lymphoid cells in the bone... (Review)
Review
UNLABELLED
: Acute lymphoblastic leukemia (ALL) is a heterogeneous group of hematologic malignancies that arise from clonal proliferation of immature lymphoid cells in the bone marrow, peripheral blood, and other organs. The vinca alkaloid vincristine is a standard component of chemotherapy regimens used to treat ALL, because of its well-defined mechanism of action, demonstrated anticancer activity, and ability to be combined with other agents. However, the dosage of vincristine is frequently capped because of neurotoxicity concerns, and patients with large body surface areas are, therefore, almost always underdosed. Liposomal formulations have the ability to "passively" accumulate at sites of increased vasculature permeability and reduce the adverse effects of encapsulated relative to free drug. Vincristine sulfate liposome injection (VSLI) is a sphingomyelin/cholesterol-based liposome-encapsulated formulation that is delivered weekly in a 1-hour infusion. Based on the pharmacokinetics of the liposomal delivery system, vincristine is slowly released from the liposome and delivered into the tissues more efficiently than with the standard preparation, allowing a higher dose. This increase in therapeutic index from reduced toxicity is a valuable difference between the two formulations. VSLI is indicated for the treatment of adults with second or greater relapse and clinically advanced Philadelphia chromosome-negative ALL. For the first time, studies will be able to exploit the delivery of higher and uncapped doses of vincristine in randomized studies comparing first-line chemotherapy with standard vincristine versus VSLI in both ALL and lymphoma to determine whether VSLI is superior to conventional vincristine.
IMPLICATIONS FOR PRACTICE
This review summarizes the development of vincristine sulfate liposome injection, a new formulation of vincristine. The pharmacokinetics of liposomal drug delivery are examined, the limitations and advantages of conventional and liposomal vincristine are compared, and the use of vincristine sulfate liposome injection in clinical trials and case studies is included. Clinicians will be informed of a new chemotherapy agent that is indicated for the treatment of adults with Philadelphia chromosome-negative acute lymphoblastic leukemia, whose disease has relapsed two or more times or whose leukemia has progressed after two or more regimens of antileukemia therapy.
Topics: Adult; Aged; Antineoplastic Agents, Phytogenic; Female; Humans; Injections; Liposomes; Male; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Vincristine
PubMed: 27328933
DOI: 10.1634/theoncologist.2015-0391 -
Cancer Genomics & Proteomics 2024The capacity for non-homologous end-joining (NHEJ) repair plays a pivotal role in maintaining genome stability and in carcinogenesis. However, there is little literature...
BACKGROUND/AIM
The capacity for non-homologous end-joining (NHEJ) repair plays a pivotal role in maintaining genome stability and in carcinogenesis. However, there is little literature on the involvement of NHEJ-related genes in childhood acute lymphocytic leukemia (ALL). Our study aimed to elucidate the impact of polymorphisms of X-ray repair cross-complementing group 4 (XRCC4) (rs6869366, rs2075685, rs2075686, rs28360071, rs3734091, rs28360317, rs1805377), XRCC5 (rs828907, rs11685387, rs9288518), XRCC6 (rs5751129, rs2267437, rs132770, rs132774), XRCC7 rs7003908, and DNA ligase IV (LIG4) rs1805388, on the odds of childhood ALL.
MATERIALS AND METHODS
Genotypes NHEJ-related genes of 266 cases and 266 controls were determined, and the genotype-phenotype correlation was investigated by examining mRNA transcript expression and the capacity for overall and precise NHEJ repair.
RESULTS
The variant genotypes of XRCC4 rs3734091, rs28360071, XRCC5 rs828907, and XRCC6 rs5751129 were significantly associated with increased odds of childhood ALL. Further analysis based on susceptibility genotypes showed no significant differences in mRNA transcript expression levels among childhood ALL cases with various putative high-risk genotypes, except XRCC6 rs5751129. Moreover, the overall NHEJ repair capacity was similar among carriers of different XRCC4, XRCC5, and XRCC6 genotypes. However, it is worth noting that individuals carrying the variant C allele at XRCC6 rs5751129 exhibited lower precise NHEJ repair capacity compared to those with the wild-type T allele.
CONCLUSION
Our study identified significant associations between XRCC4 rs3734091, rs28360071, XRCC5 rs828907, and XRCC6 rs5751129 genotypes and childhood ALL. Notably, lower transcriptional expression and reduced precise NHEJ repair capacity were observed in patients carrying the C allele of XRCC6 rs5751129. Further investigations are required to gain deeper insights into childhood ALL development.
Topics: Humans; Genotype; Alleles; Precursor Cell Lymphoblastic Leukemia-Lymphoma; DNA Repair; RNA, Messenger; Genetic Predisposition to Disease; Case-Control Studies; Polymorphism, Single Nucleotide
PubMed: 38423600
DOI: 10.21873/cgp.20436 -
Leukemia Sep 2016Children with Down syndrome (DS) are at a 20-fold increased risk for acute lymphoblastic leukemia (DS-ALL). Although the etiology of this higher risk of developing... (Review)
Review
Children with Down syndrome (DS) are at a 20-fold increased risk for acute lymphoblastic leukemia (DS-ALL). Although the etiology of this higher risk of developing leukemia remains largely unclear, the recent identification of CRLF2 (cytokine receptor like factor 2) and JAK2 mutations and study of the effect of trisomy of Hmgn1 and Dyrk1a (dual-specificity tyrosine phosphorylation-regulated kinase 1A) on B-cell development have shed significant new light on the disease process. Here we focus on the clinical features, biology and genetics of ALL in children with DS. We review the unique characteristics of DS-ALL on both the clinical and molecular levels and discuss the differences in treatments and outcomes in ALL in children with DS compared with those without DS. The identification of new biological insights is expected to pave the way for novel targeted therapies.
Topics: B-Lymphocytes; Child; Down Syndrome; Humans; Molecular Targeted Therapy; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Treatment Outcome
PubMed: 27285583
DOI: 10.1038/leu.2016.164