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

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.

Fig. 1. Soluble biomarkers secreted to cerebrospinal fluid or hypothesized to prime CNS compartments for transmigration of leukemic cells.

Biomarkers may comprise leukemic-derived vesicles, secreted proteins and metabolites, or cell-free DNA.

Fig. 2. Mechanisms of action of drugs that target leukemic cells within the CNS.

A Coronal section of human brain showing the meninges and the meningeal vasculature. The leptomeninges consist of the arachnoid mater, the pia mater and the subarachnoid space. The subarachnoid space is filled with CSF, veins, arteries and arachnoid trabeculae extending from the arachnoid mater to the pia mater. B Novel drugs that target survival mechanisms employed by leukemia cells in the leptomeninges [1]. Sorafenib and selumetinib inhibit Ras/Raf/MEK/ERK signaling downstream of B-cell receptor activation [2] Dasatinib inhibit LCK signaling downstream of T-cell receptor activation [3]. Bevacizumab sequesters VEGF-A and inhibit binding to the VEGFR2 [4]. SW103668 inhibit SCD-mediated enzymatic conversion of saturated fatty acids to mono-unsaturated fatty acids and OMA inhibit ribosome mRNA translation [5]. Me6TREN inhibit adhesion of leukemia cells to meningeal cells. C Novel drugs that target invasion mechanisms employed by leukemia cells during dissemination to the leptomeninges [1]. Copansilib inhibit integrin α6-mediated migration of leukemia cells along emissary vessels [2]. Plerixafor or BL-8040 block CRCX4-mediated migration across meningeal blood vessels. LCK lymphocyte specific cell-kinase, CNS central nervous system, CSF cerebrospinal fluid, SCD stearoyl-CoA desaturase, VEGF vascular endothelial factor, OMA omacetaxine mepesuccinate.