Invasive fungal disease and antifungal prophylaxis in children with acute leukaemia: a multicentre retrospective Australian cohort study.

Background: Invasive fungal disease (IFD) is a significant complication for children receiving treatment for leukaemia, contributing to morbidity and mortality. Recent regional paediatric epidemiological IFD data are lacking. Additionally uncertainty remains regarding the optimal prophylactic approach in this context.

Challenges and considerations for antifungal prophylaxis in children with acute myeloid leukemia.

Introduction: Children receiving treatment for acute myeloid leukemia (AML) are at high risk of invasive fungal disease (IFD). Evidence from pediatric studies support the efficacy of antifungal prophylaxis in reducing the burden of IFD in children receiving therapy for AML, yet existing antifungal agents have specific limitations and comparative data to inform the optimal prophylactic approach are lacking.

Areas Covered: This review summarizes the epidemiology of invasive fungal disease (IFD) and current antifungal prophylaxis recommendations for children with acute myeloid leukemia (AML).

Down syndrome-associated leukaemias: current evidence and challenges.

Children with Down syndrome (DS) are at increased risk of developing haematological malignancies, in particular acute megakaryoblastic leukaemia and acute lymphoblastic leukaemia. The microenvironment established by abnormal haematopoiesis driven by trisomy 21 is compounded by additional genetic and epigenetic changes that can drive leukaemogenesis in patients with DS. GATA-binding protein 1 () somatic mutations are implicated in the development of transient abnormal myelopoiesis and the progression to myeloid leukaemia of DS (ML-DS) and provide a model of the multi-step process of leukaemogenesis in DS.

Insights into the Clinical, Biological and Therapeutic Impact of Copy Number Alteration in Cancer.

Copy number alterations (CNAs), resulting from the gain or loss of genetic material from as little as 50 base pairs or as big as entire chromosome(s), have been associated with many congenital diseases, de novo syndromes and cancer. It is established that CNAs disturb the dosage of genomic regions including enhancers/promoters, long non-coding RNA and gene(s) among others, ultimately leading to an altered balance of key cellular functions. In cancer, CNAs have been associated with almost all steps of the disease: predisposition, initiation, development, maintenance, response to treatment, resistance, and relapse.

Murine bone-derived mesenchymal stem cells undergo molecular changes after a single passage in culture.

The rarity of the mesenchymal stem cell (MSC) population poses a significant challenge for MSC research. Therefore, these cells are often expanded in vitro, prior to use. However, long-term culture has been shown to alter primary MSC properties.

Minimising Adverse Drug Reactions and Verifying Economic Legitimacy-Pharmacogenomics Implementation in Children (MARVEL- PIC): protocol for a national randomised controlled trial of pharmacogenomics implementation.

Introduction: DNA-informed prescribing (termed pharmacogenomics, PGx) is the epitome of personalised medicine. Despite international guidelines existing, its implementation in paediatric oncology remains sparse.

Methods And Analysis: Minimising Adverse Drug Reactions and Verifying Economic Legitimacy-Pharmacogenomics Implementation in Children is a national prospective, multicentre, randomised controlled trial assessing the impact of pre-emptive PGx testing for actionable PGx variants on adverse drug reaction (ADR) incidence in patients with a new cancer diagnosis or proceeding to haematopoetic stem cell transplant.

Combining CRISPR-Cas9 and TCR exchange to generate a safe and efficient cord blood-derived T cell product for pediatric relapsed AML.

Background: Hematopoietic cell transplantation (HCT) is an effective treatment for pediatric patients with high-risk, refractory, or relapsed acute myeloid leukemia (AML). However, a large proportion of transplanted patients eventually die due to relapse. To improve overall survival, we propose a combined strategy based on cord blood (CB)-HCT with the application of AML-specific T cell receptor (TCR)-engineered T cell therapy derived from the same CB graft.

The critical role of the bone marrow stromal microenvironment for the development of drug screening platforms in leukemia.

Extensive research over the past 50 years has resulted in significant improvements in survival for patients diagnosed with leukemia. Despite this, a subgroup of patients harboring high-risk genetic alterations still suffer from poor outcomes. There is a desperate need for new treatments to improve survival, yet consistent failure exists in the translation of in vitro drug development to clinical application.

Pharmacokinetics of PEGasparaginase in Infants with Acute Lymphoblastic Leukemia.

Background: PEGasparaginase is known to be a critical drug for treating pediatric acute lymphoblastic leukemia (ALL), however, there is insufficient evidence to determine the optimal dose for infants who are less than one year of age at diagnosis. This international study was conducted to identify the pharmacokinetics of PEGasparaginase in infants with newly diagnosed ALL and gather insight into the clearance and dosing of this population.

Methods: Infants with ALL who received treatment with PEGasparaginase were included in our population pharmacokinetic assessment employing non-linear mixed effects modelling (NONMEM).

Biologic and clinical features of childhood gamma delta T-ALL: identification of STAG2/LMO2 γδ T-ALL as an extremely high risk leukemia in the very young.

Purpose: Gamma delta T-cell receptor-positive acute lymphoblastic leukemia (γδ T-ALL) is a high-risk but poorly characterized disease.

Methods: We studied clinical features of 200 pediatric γδ T-ALL, and compared the prognosis of 93 cases to 1,067 protocol-matched non-γδ T-ALL. Genomic features were defined by transcriptome and genome sequencing.

Reproducible Bioinformatics Analysis Workflows for Detecting Gene Fusions in B-Cell Acute Lymphoblastic Leukaemia Patients.

B-cell acute lymphoblastic leukaemia (B-ALL) is characterised by diverse genomic alterations, the most frequent being gene fusions detected via transcriptomic analysis (mRNA-seq). Due to its hypervariable nature, gene fusions involving the Immunoglobulin Heavy Chain () locus can be difficult to detect with standard gene fusion calling algorithms and significant computational resources and analysis times are required. We aimed to optimize a gene fusion calling workflow to achieve best-case sensitivity for gene fusion detection.

Delivery of PEGylated liposomal doxorubicin by bispecific antibodies improves treatment in models of high-risk childhood leukemia.

High-risk childhood leukemia has a poor prognosis because of treatment failure and toxic side effects of therapy. Drug encapsulation into liposomal nanocarriers has shown clinical success at improving biodistribution and tolerability of chemotherapy. However, enhancements in drug efficacy have been limited because of a lack of selectivity of the liposomal formulations for the cancer cells.

Blinatumomab Added to Chemotherapy in Infant Lymphoblastic Leukemia.

Background: -rearranged acute lymphoblastic leukemia (ALL) in infants is an aggressive disease with 3-year event-free survival below 40%. Most relapses occur during treatment, with two thirds occurring within 1 year and 90% within 2 years after diagnosis. Outcomes have not improved in recent decades despite intensification of chemotherapy.

Pre-Clinical Evaluation of the Hypomethylating Agent Decitabine for the Treatment of T-Cell Lymphoblastic Lymphoma.

T-cell lymphoblastic lymphoma (T-LBL) is a rare and aggressive lymphatic cancer, often diagnosed at a young age. Patients are treated with intensive chemotherapy, potentially followed by a hematopoietic stem cell transplantation. Although prognosis of T-LBL has improved with intensified treatment protocols, they are associated with side effects and 10-20% of patients still die from relapsed or refractory disease.

Characterization of mesenchymal stem cells in pre-B acute lymphoblastic leukemia.

Components of the bone marrow microenvironment (BMM) have been shown to mediate the way in which leukemia develops, progresses and responds to treatment. Increasing evidence shows that leukemic cells hijack the BMM, altering its functioning and establishing leukemia-supportive interactions with stromal and immune cells. While previous work has highlighted functional defects in the mesenchymal stem cell (MSC) population from the BMM of acute leukemias, thorough characterization and molecular profiling of MSCs in pre-B cell acute lymphoblastic leukemia (B-ALL), the most common cancer in children, has not been conducted.

Survival outcomes of children with relapsed or refractory myeloid leukemia associated with Down syndrome.

Children with Down syndrome (DS) are at a significantly higher risk of developing acute myeloid leukemia, also termed myeloid leukemia associated with DS (ML-DS). In contrast to the highly favorable prognosis of primary ML-DS, the limited data that are available for children who relapse or who have refractory ML-DS (r/r ML-DS) suggest a dismal prognosis. There are few clinical trials and no standardized treatment approach for this population.

Lessons learnt from influenza vaccination in immunocompromised children undergoing treatment for cancer.

Influenza infection contributes substantially to global morbidity and mortality, with children undergoing treatment for cancer among the most vulnerable due to immunosuppression associated with disease and treatment. However, influenza remains one of the most common vaccine-preventable diseases. Despite international guidelines recommending inactivated influenza vaccination on the basis of data supporting efficacy and an excellent safety profile in this population, uptake has often been suboptimal due to persisting hesitancy among both patients and oncologists regarding the ability of the vaccine to mount a sufficient immune response, the optimal vaccine schedule and timing, and the best method to assess response in immunocompromised populations.

Cardio-Oncology Recommendations for Pediatric Oncology Patients: An Australian and New Zealand Delphi Consensus.

Cardio-oncology is a new multidisciplinary area of expertise that seeks to pre-emptively and proactively address cardiac complications that emerge during and following cancer therapy. Modern therapies including molecular targeted therapy and immunotherapy have broadened the agents that can cause cardiac sequelae, often with complications arising within days to weeks of therapy. Several international guidelines have been developed for the acute monitoring of cardio-oncology side effects.