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      Targeted Therapies for Pediatric AML: Gaps and Perspective

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          Abstract

          Acute myeloid leukemia (AML) is a hematopoietic disorder characterized by numerous cytogenetic and molecular aberrations that accounts for ~25% of childhood leukemia diagnoses. The outcome of children with AML has increased remarkably over the past 30 years, with current survival rates up to 70%, mainly due to intensification of standard chemotherapy and improvements in risk classification, supportive care, and minimal residual disease monitoring. However, childhood AML prognosis remains unfavorable and relapse rates are still around 30%. Therefore, novel therapeutic approaches are needed to increase the cure rate. In AML, the presence of gene mutations and rearrangements prompted the identification of effective targeted molecular strategies, including kinase inhibitors, cell pathway inhibitors, and epigenetic modulators. This review will discuss several new drugs that recently received US Food and Drug Administration approval for AML treatment and promising strategies to treat childhood AML, including FLT3 inhibitors, epigenetic modulators, and Hedgehog pathway inhibitors.

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          Most cited references76

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          Potent inhibition of DOT1L as treatment of MLL-fusion leukemia.

          Rearrangements of the MLL gene define a genetically distinct subset of acute leukemias with poor prognosis. Current treatment options are of limited effectiveness; thus, there is a pressing need for new therapies for this disease. Genetic and small molecule inhibitor studies have demonstrated that the histone methyltransferase DOT1L is required for the development and maintenance of MLL-rearranged leukemia in model systems. Here we describe the characterization of EPZ-5676, a potent and selective aminonucleoside inhibitor of DOT1L histone methyltransferase activity. The compound has an inhibition constant value of 80 pM, and demonstrates 37 000-fold selectivity over all other methyltransferases tested. In cellular studies, EPZ-5676 inhibited H3K79 methylation and MLL-fusion target gene expression and demonstrated potent cell killing that was selective for acute leukemia lines bearing MLL translocations. Continuous IV infusion of EPZ-5676 in a rat xenograft model of MLL-rearranged leukemia caused complete tumor regressions that were sustained well beyond the compound infusion period with no significant weight loss or signs of toxicity. EPZ-5676 is therefore a potential treatment of MLL-rearranged leukemia and is under clinical investigation.
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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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              Advances in cancer immunotherapy 2019 – latest trends

              Immunotherapy has become an established pillar of cancer treatment improving the prognosis of many patients with a broad variety of hematological and solid malignancies. The two main drivers behind this success are checkpoint inhibitors (CPIs) and chimeric antigen receptor (CAR) T cells. This review summarizes seminal findings from clinical and translational studies recently presented or published at important meetings or in top-tier journals, respectively. For checkpoint blockade, current studies focus on combinational approaches, perioperative use, new tumor entities, response prediction, toxicity management and use in special patient populations. Regarding cellular immunotherapy, recent studies confirmed safety and efficacy of CAR T cells in larger cohorts of patients with acute lymphoblastic leukemia or diffuse large B cell lymphoma. Different strategies to translate the striking success of CAR T cells in B cell malignancies to other hematological and solid cancer types are currently under clinical investigation. Regarding the regional distribution of registered clinical immunotherapy trials a shift from PD-1 / PD-L1 trials (mainly performed in the US and Europe) to CAR T cell trials (majority of trials performed in the US and China) can be noted.
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                Author and article information

                Contributors
                Journal
                Front Pediatr
                Front Pediatr
                Front. Pediatr.
                Frontiers in Pediatrics
                Frontiers Media S.A.
                2296-2360
                15 November 2019
                2019
                : 7
                : 463
                Affiliations
                [1] 1“Giorgio Prodi” Interdepartmental Cancer Research Centre, University of Bologna , Bologna, Italy
                [2] 2Pediatric Hematology-Oncology Unit, Department of Medical and Surgical Sciences DIMEC, University of Bologna , Bologna, Italy
                Author notes

                Edited by: Sarah K. Tasian, University of Pennsylvania, United States

                Reviewed by: Yana Pikman, Dana–Farber Cancer Institute, United States; Christian Michel Zwaan, Sophia Children's Hospital, Netherlands; Henrik Hasle, Aarhus University, Denmark

                *Correspondence: Annalisa Lonetti annalisa.lonetti2@ 123456unibo.it

                This article was submitted to Pediatric Hematology and Hematological Malignancies, a section of the journal Frontiers in Pediatrics

                Article
                10.3389/fped.2019.00463
                6873958
                31803695
                3c2bdc9e-9d81-411f-a052-fbcb5d478b1e
                Copyright © 2019 Lonetti, Pession and Masetti.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 18 July 2019
                : 24 October 2019
                Page count
                Figures: 1, Tables: 1, Equations: 0, References: 92, Pages: 11, Words: 9120
                Funding
                Funded by: Associazione Italiana per la Ricerca sul Cancro 10.13039/501100005010
                Award ID: MFAG2016
                Categories
                Pediatrics
                Review

                pediatric aml,targeted therapy,flt-3 inhibitors,hedgehog pathway inhibitors,dot1l inhibitors

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