Epidemiology of Therapy-Related Myeloid Neoplasms After Treatment for Pediatric Acute Lymphoblastic Leukemia in the Nordic Countries.

Of 1614 Nordic children with ALL that were treated according to the NOPHO ALL92 protocol, 20 developed an SMN (cumulative risk at 12 years: 1.6%). Sixteen of the twenty SMNs were acute myeloid leukemias or myelodysplasias, and 9 of these had either monosomy 7 (n=7) or 7q deletions (n=2). In Cox multivariate analysis longer duration of oral MTX/6MP maintenance therapy (p=0.02; being longest for standard risk patients) and presence of high-hyperdiploidy (p=0.07) were related to an increased risk of SMN. In 524 patients we determined the erythrocyte activity of thiopurine methyltransferase (TPMT), which methylates 6MP and its metabolites, and thus reduces cellular levels of cytotoxic 6-thioguanine nucleotides. The TPMT activity was significantly lower in those that did compared to those that did not develop an SMN (Median: 12.1 vs 18.1 IU/ml; p=0.02). Among 427 TPMT wild type patients, those who developed SMN received higher 6MP doses than the remaining (69.7 vs 60.4 mg/m2, p=0.03), which may reflect increased levels of methylated metabolites that inhibit purine de novo synthesis and thus enhance incorporation of 6-thioguanine nucleotides into DNA. In conclusion, the duration and intensity of 6MP/MTX maintenance therapy of childhood ALL may influence the risk of SMN

Challenges in implementing individualized medicine illustrated by antimetabolite therapy of childhood acute lymphoblastic leukemia

Predicting the response to medical therapy and subsequently individualizing the treatment to increase efficacy or reduce toxicity has been a longstanding clinical goal. Not least within oncology, where many patients fail to be cured, and others are treated to or beyond the limit of acceptable toxicity, an individualized therapeutic approach is indicated. The mapping of the human genome and technological developments in DNA sequencing, gene expression profiling, and proteomics have raised the expectations for implementing genotype-phenotype data into the clinical decision process, but also multiplied the complex interaction of genetic and other laboratory parameters that can be used for therapy adjustments. Thus, with the advances in the laboratory techniques, post laboratory issues have become major obstacles for treatment individualization. Many of these challenges have been illustrated by studies involving childhood acute lymphoblastic leukemia (ALL), where each patient may receive up to 13 different anticancer agents over a period of 2-3 years. The challenges include i) addressing important, but low-frequency outcomes, ii) difficulties in interpreting the impact of single drug or single gene response data that often vary across treatment protocols, iii) combining disease and host genomics with outcome variations, and iv) physicians' reluctance in implementing potentially useful genotype and phenotype data into clinical practice, since unjustified downward or upward dose adjustments could increase the of risk of relapse or life-threatening complications. In this review we use childhood ALL therapy as a model and discuss these issues, and how they may be addressed

Social Inequalities Along the Childhood Cancer Continuum:An Overview of Evidence and a Conceptual Framework to Identify Underlying Mechanisms and Pathways

Inequalities in health according to social conditions are regarded as unnecessary and unjust. There is a large body of evidence on inequalities in adult cancer, observable throughout the societies on a national level as well as on a global scale. Socioeconomic influences on health matter at all ages including childhood, for which childhood cancer is the leading cause of disease related death in high-income countries (HICs). Substantial differences in the reported incidence of childhood cancers have been observed globally by socioeconomic development of a population. This is reflected in the higher incidence rates reported for HICs, particularly for acute lymphoblastic leukemia, and for cancer in infants (below 1 year), compared to low- and middle-income countries (LMICs). Considerable inequalities between populations and degree of socioeconomic development are also noted for survival from childhood cancer, with substantially lower survival rates seen in most LMICs compared to HICs. With respect to inequalities by socioeconomic position (SEP) within countries, findings of an association between SEP and childhood cancer risk are diverse and limited to studies from HICs. On the contrary, observations on social inequalities in survival within countries are accumulating and indicate that survival inequalities do not only concern resource-poor countries but also high-income populations including European countries. In turn, a childhood cancer diagnosis in itself may have implications on the parents' socioeconomic situation as well as on the later socioeconomic life after having survived the disease. The underlying mechanisms and causal pathways of these empirically demonstrated social inequalities are poorly understood, although it is of significant public health relevance for any actions or strategies to reduce childhood cancer-related inequity. We propose a conceptual framework on potential underlying mechanism and pathways specifically addressing social inequalities in childhood cancer and after childhood cancer to (i) illustrate potential pathways by which social determinants may create health inequities at different points of the childhood cancer continuum; (ii) illustrate potential pathways by which a childhood cancer diagnosis may impact the socioeconomic situation of the concerned family or the later life of a childhood survivor; and (iii) point out how major determinants may relate to each other

Telepresence robotic technology support for social connectedness during treatment of children with cancer

Children with cancer experience fragmented school attendance during treatment. Telepresence robots that connect them with school during treatment periods were explored through an intervention involving participant observation followed by semi-structured interviews from 2020–22 with children with cancer, their class teachers, and classmates. We used an abductive approach, inspired by the Agential Realism theory and Situational Analysis. The use of telepresence robots in education enables hospitalized children to actively participate in real-time social activities with their classmates. However, consistent monitoring is necessary to ensure the success of this integration process as the classmates can lose interest in providing support to a child with cancer.</p

Central nervous system involvement in childhood acute lymphoblastic leukemia: challenges and solutions

Delivery of effective anti-leukemic agents to the central nervous system (CNS) is considered essential for cure of childhood acute lymphoblastic leukemia. Current CNS-directed therapy comprises systemic therapy with good CNS-penetration accompanied by repeated intrathecal treatments up to 26 times over 2–3 years. This approach prevents most CNS relapses, but is associated with significant short and long term neurotoxicity. Despite this burdensome therapy, there have been no new drugs licensed for CNS-leukemia since the 1960s, when very limited anti-leukemic agents were available and there was no mechanistic understanding of leukemia survival in the CNS. Another major barrier to improved treatment is that we cannot accurately identify children at risk of CNS relapse, or monitor response to treatment, due to a lack of sensitive biomarkers. A paradigm shift in treating the CNS is needed. The challenges are clear – we cannot measure CNS leukemic load, trials have been unable to establish the most effective CNS treatment regimens, and non-toxic approaches for relapsed, refractory, or intolerant patients are lacking. In this review we discuss these challenges and highlight research advances aiming to provide solutions. Unlocking the potential of risk-adapted non-toxic CNS-directed therapy requires; (1) discovery of robust diagnostic, prognostic and response biomarkers for CNS-leukemia, (2) identification of novel therapeutic targets combined with associated investment in drug development and early-phase trials and (3) engineering of immunotherapies to overcome the unique challenges of the CNS microenvironment. Fortunately, research into CNS-ALL is now making progress in addressing these unmet needs: biomarkers, such as CSF-flow cytometry, are now being tested in prospective trials, novel drugs are being tested in Phase I/II trials, and immunotherapies are increasingly available to patients with CNS relapses. The future is hopeful for improved management of the CNS over the next decade

Participation, challenges and needs in children with down syndrome during cancer treatment at hospital: a qualitative study of parents' experiences

BackgroundStudies report that it can be challenging to assess and treat side-effects and symptoms among children who have impairments and difficulties in expressing their needs. Children with Down syndrome have an increased vulnerability and an increased risk for contracting leukaemia. There is sparse knowledge about the parental experience of how treatment and side-effects affect children with Down syndrome with leukaemia, as well as the role of participation during treatment.PurposeThis study aimed to explore the perceptions of parents of children with Down syndrome and leukaemia regarding their child's treatment, side effects and participation during hospital care.MethodsA qualitative study design was used, and interviews were conducted with a semi-structured interview-guide. Fourteen parents of 10 children with Down syndrome and acute lymphoblastic leukaemia from Sweden and Denmark, 1–18 years of age, participated. All children had completed therapy or had a few months left before the end of treatment. Data was analysed according to qualitative content analysis.ResultsFour sub-themes were identified: (1) Continuously dealing with the child's potential susceptibility; (2) Confidence and worries regarding decisions related to treatment regulation; (3) Challenges in communication, interpretation, and participation; and (4) Facilitating participation by adapting to the child's behavioural and cognitive needs. The sub-themes were bound together in an overarching theme, which expressed the core perception “Being the child's spokesperson to facilitate the child's participation during treatment”. The parents expressed this role as self-evident to facilitate communication regarding the needs of the child, but also regarding how the cytotoxic treatment affected the vulnerable child. Parents conveyed the struggle to ensure the child's right to receive optimal treatment.ConclusionThe study results highlight parental challenges regarding childhood disabilities and severe health conditions, as well as communication and ethical aspects regarding to act in the best interests of the child. Parents played a vital role in interpreting their child with Down syndrome. Involving parents during treatment enables a more accurate interpretation of symptoms and eases communication and participation. Still, the results raise questions regarding issues related to building trust in healthcare professionals in a context where medical, psychosocial and ethical dilemmas are present