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      Omics-based insights into therapy failure of pediatric B-lineage acute lymphoblastic leukemia

      research-article
      Oncology Reviews
      PAGEPress Publications, Pavia, Italy
      Pediatric B-ALL, therapy failure, omics

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          Abstract

          B-lineage acute lymphoblastic leukemia (B-ALL) is the most common type of cancer seen in children and is characterized by a variable clinical course. Although there have been remarkable improvements in the therapy outcomes of pediatric B-ALL, treatment failure remains the leading-cause of death in 18% of the afflicted patients during the first 5 years after diagnosis. Molecular heterogeneities of pediatric B-ALL play important roles as determinants of the therapy response. Therefore, many of these molecular abnormalities have an established prognostic value in the disease. The present review discusses the omics-based revelations from epigenomics, genomics, transcriptomics and proteomics about treatment failure in pediatric B-ALL. Next it highlights the promise of the molecular aberration-targeted therapy to improve the treatment outcomes.

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          Most cited references54

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          Acute lymphoblastic leukaemia.

          Acute lymphoblastic leukaemia occurs in both children and adults but its incidence peaks between 2 and 5 years of age. Causation is multifactorial and exogenous or endogenous exposures, genetic susceptibility, and chance have roles. Survival in paediatric acute lymphoblastic leukaemia has improved to roughly 90% in trials with risk stratification by biological features of leukaemic cells and response to treatment, treatment modification based on patients' pharmacodynamics and pharmacogenomics, and improved supportive care. However, innovative approaches are needed to further improve survival while reducing adverse effects. Prognosis remains poor in infants and adults. Genome-wide profiling of germline and leukaemic cell DNA has identified novel submicroscopic structural genetic changes and sequence mutations that contribute to leukaemogenesis, define new disease subtypes, affect responsiveness to treatment, and might provide novel prognostic markers and therapeutic targets for personalised medicine. Copyright © 2013 Elsevier Ltd. All rights reserved.
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            Treating childhood acute lymphoblastic leukemia without cranial irradiation.

            Prophylactic cranial irradiation has been a standard treatment in children with acute lymphoblastic leukemia (ALL) who are at high risk for central nervous system (CNS) relapse. We conducted a clinical trial to test whether prophylactic cranial irradiation could be omitted from treatment in all children with newly diagnosed ALL. A total of 498 patients who could be evaluated were enrolled. Treatment intensity was based on presenting features and the level of minimal residual disease after remission-induction treatment. The duration of continuous complete remission in the 71 patients who previously would have received prophylactic cranial irradiation was compared with that of 56 historical controls who received it. The 5-year event-free and overall survival probabilities for all 498 patients were 85.6% (95% confidence interval [CI], 79.9 to 91.3) and 93.5% (95% CI, 89.8 to 97.2), respectively. The 5-year cumulative risk of isolated CNS relapse was 2.7% (95% CI, 1.1 to 4.3), and that of any CNS relapse (including isolated relapse and combined relapse) was 3.9% (95% CI, 1.9 to 5.9). The 71 patients had significantly longer continuous complete remission than the 56 historical controls (P=0.04). All 11 patients with isolated CNS relapse remained in second remission for 0.4 to 5.5 years. CNS leukemia (CNS-3 status) or a traumatic lumbar puncture with blast cells at diagnosis and a high level of minimal residual disease (> or = 1%) after 6 weeks of remission induction were significantly associated with poorer event-free survival. Risk factors for CNS relapse included the genetic abnormality t(1;19)(TCF3-PBX1), any CNS involvement at diagnosis, and T-cell immunophenotype. Common adverse effects included allergic reactions to asparaginase, osteonecrosis, thrombosis, and disseminated fungal infection. With effective risk-adjusted chemotherapy, prophylactic cranial irradiation can be safely omitted from the treatment of childhood ALL. (ClinicalTrials.gov number, NCT00137111.) 2009 Massachusetts Medical Society
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              Biology, risk stratification, and therapy of pediatric acute leukemias: an update.

              We review recent advances in the biologic understanding and treatment of childhood acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), identify therapeutically challenging subgroups, and suggest future directions of research. A review of English literature on childhood acute leukemias from the past 5 years was performed. Contemporary treatments have resulted in 5-year event-free survival rates of approximately 80% for childhood ALL and almost 60% for pediatric AML. The advent of high-resolution genome-wide analyses has provided new insights into leukemogenesis and identified many novel subtypes of leukemia. Virtually all ALL and the vast majority of AML cases can be classified according to specific genetic abnormalities. Cooperative mutations involved in cell differentiation, cell cycle regulation, tumor suppression, drug responsiveness, and apoptosis have also been identified in many cases. The development of new formulations of existing drugs, molecularly targeted therapy, and immunotherapies promises to further advance the cure rates and improve quality of life of patients. The application of new high-throughput sequencing techniques to define the complete DNA sequence of leukemia and host normal cells and the development of new agents targeted to leukemogenic pathways promise to further improve outcome in the coming decade.
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                Author and article information

                Journal
                Oncol Rev
                Oncol Rev
                ONCOL
                Oncology Reviews
                PAGEPress Publications, Pavia, Italy
                1970-5565
                1970-5557
                10 September 2019
                22 July 2019
                : 13
                : 2
                : 435
                Affiliations
                Department of Medical Laboratories Sciences, College of Applied Medical Sciences, Majmaah University , Saudi Arabia
                Author notes
                Department of Medical Laboratories Sciences, College of Applied Medical Sciences, Majmaah University, PO Box 1712, Majmaah 11932, Saudi Arabia. +966.542552749. s.alsaqaby@ 123456mu.edu.sa

                Conflict of interest: the author reports no conflicts of interest.

                Article
                10.4081/oncol.2019.435
                6747058
                df175e1c-6677-4f02-9d64-3dc62fb95fd2
                ©Copyright: the Author(s), 2019

                This work is licensed under a Creative Commons Attribution NonCommercial 4.0 License (CC BY-NC 4.0).

                History
                : 10 June 2019
                : 20 August 2019
                Page count
                Figures: 0, Tables: 1, Equations: 0, References: 71, Pages: 7
                Categories
                Review

                pediatric b-all,therapy failure,omics
                pediatric b-all, therapy failure, omics

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