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.

Case Report: Blinatumomab therapy for the treatment of B-cell acute lymphoblastic leukemia patients with central nervous system infiltration

“…BM smear revealed 88.76% of blasts, which were CD10+/CD13-/CD19+/CD20-/CD22±/CD33-/CD34+/CD38+ by FCM. Cytogenetics was 47, XY, add(1)(q42), +8 [3]/47, idem, add(5)(q13), add(9)(p22) [12]/46, XY [5]. NRAS p.Gly13Arg, p.Gln61Arg, p.Gln61Lys mutations were identified by NGS.…”

“…Treatment of CNS leukemia is very challenging due to the impermeability of many systemic therapies to the blood-brain barrier (BBB). CNS-targeted therapy includes intrathecal chemotherapy, cranial radiotherapy, and chemotherapy with high-dose cytarabine or high-dose methotrexate ( 5 ). Intrathecal chemotherapy can only penetrate 1-2 mm of tissue and is ineffective when leukemic cells infiltrate deep into the cerebral parenchymal ( 2 ).…”

The CNS Microenvironment Promotes Leukemia Cell Survival by Disrupting Tumor Suppression and Cell Cycle Regulation in Pediatric T-cell Acute Lymphoblastic Leukemia

“…However, mechanisms promoting increased survival are not well understood. Therefore, we exposed T-ALL cells to MTX, a chemotherapeutic agent commonly used to treat CNS disease in T-ALL [4]. Cells were treated with 2μM of MTX, both in suspension and when grown adherent to glioblastoma cells, followed by RT-qPCR to evaluate effects on mRNA expression.…”

“…To date, CNS directed therapy is given as a prophylactic treatment to prevent CNS relapse, regardless of CNS involvement at the time of diagnosis. However, CNS directed therapy causes detrimental adverse effects and neurocognitive impairments, as well as increasing the risk of secondary malignancies in the CNS [4]. Due to lack of knowledge of the mechanisms promoting leukemia survival in the CNS microenvironment, no new CNS directed treatments have been developed since the 1960’s, yet the treatment is considered essential for complete cure [4].…”

“…However, CNS directed therapy causes detrimental adverse effects and neurocognitive impairments, as well as increasing the risk of secondary malignancies in the CNS [4]. Due to lack of knowledge of the mechanisms promoting leukemia survival in the CNS microenvironment, no new CNS directed treatments have been developed since the 1960’s, yet the treatment is considered essential for complete cure [4]. Thus, there is a need for reliable biomarkers to properly predict and monitor disease progression and CNS involvement to identify high risk patients, thus minimizing the risk of overtreatment and neurotoxic effects.…”