Thastrup, M., Duguid, A., Mirian, C., Schmiegelow, K. and Halsey, C. (2022) Central nervous system involvement in childhood acute lymphoblastic leukemia: challenges and solutions. Leukemia, 36(12), pp. 2751-2768. (doi: 10.1038/s41375-022-01714-x) (PMID:36266325)
![[img]](https://eprints.gla.ac.uk/style/images/fileicons/text.png) |
Text
279469.pdf - Published Version Available under License Creative Commons Attribution. 1MB |
Abstract
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.
| Item Type: | Articles |
|---|---|
| Additional Information: | This work was supported by the UK Childrens Cancer and Leukaemia Group/Little Princess Trust (CCLGA 2020-24 & 2020-11) & Children with Cancer UK (CwCUK 14-170) to CH, Cancer Research UK Clinical Research Fellowship (C60521/A31315) to AD, the Danish Childhood Cancer Foundation (2020-6828 and 2021-7412) to MT, The Research Fund of Rigshospitalet, Copenhagen University Hospital (22093-09) to CM and the Novo Nordisk Foundation (NNF18OC0052813) to KS. |
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Halsey, Professor Chris and Duguid, Dr Alasdair |
| Authors: | Thastrup, M., Duguid, A., Mirian, C., Schmiegelow, K., and Halsey, C. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Cancer Sciences |
| Journal Name: | Leukemia |
| Publisher: | Springer Nature |
| ISSN: | 0887-6924 |
| ISSN (Online): | 1476-5551 |
| Published Online: | 20 October 2022 |
| Copyright Holders: | Copyright © 2022 The Authors |
| First Published: | First published in Leukemia 36(12): 2751-2768 |
| Publisher Policy: | Reproduced under a Creative Commons License |
University Staff: Request a correction | Enlighten Editors: Update this record
Funder and Project Information
Funder and Project Information