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Pharmacogenetics of the Central Nervous System-Toxicity and Relapse Affecting the CNS in Pediatric Acute Lymphoblastic Leukemia.

ABSTRACT: Despite improving cure rates in childhood acute lymphoblastic leukemia (ALL), therapeutic side effects and relapse are ongoing challenges. These can also affect the central nervous system (CNS). Our aim was to identify germline gene polymorphisms that influence the risk of CNS events. Sixty single nucleotide polymorphisms (SNPs) in 20 genes were genotyped in a Hungarian non-matched ALL cohort of 36 cases with chemotherapy related acute toxic encephalopathy (ATE) and 544 controls. Five significant SNPs were further analyzed in an extended Austrian-Czech-NOPHO cohort (n = 107 cases, n = 211 controls) but none of the associations could be validated. Overall populations including all nations' matched cohorts for ATE (n = 426) with seizure subgroup (n = 133) and posterior reversible encephalopathy syndrome (PRES, n = 251) were analyzed, as well. We found that patients with ABCB1 rs1045642, rs1128503 or rs2032582 TT genotypes were more prone to have seizures but those with rs1045642 TT developed PRES less frequently. The same SNPs were also examined in relation to ALL relapse on a case-control matched cohort of 320 patients from all groups. Those with rs1128503 CC or rs2032582 GG genotypes showed higher incidence of CNS relapse. Our results suggest that blood-brain-barrier drug transporter gene-polymorphisms might have an inverse association with seizures and CNS relapse.

SUBMITTER: Sagi JC

PROVIDER: S-EPMC8151239 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundRefractory central nervous system (CNS) involvement is among the major causes of therapy failure in childhood acute leukemia. Applying contemporary diagnostic methods, CNS disease is often underdiagnosed. To explore more sensitive and less invasive CNS status indicators, we examined microRNA (miR) expressions and extracellular vesicle (EV) characteristics.MethodsIn an acute lymphoblastic leukemia (ALL) discovery cohort, 47 miRs were screened using Custom TaqMan Advanced Low-Density Array gene expression cards. As a validation step, a candidate miR family was further scrutinized with TaqMan Advanced miRNA Assays on serial cerebrospinal fluid (CSF), bone marrow (BM) and peripheral blood samples with different acute leukemia subtypes. Furthermore, small EV-rich fractions were isolated from CSF and the samples were processed for immunoelectron microscopy with anti-CD63 and anti-CD81 antibodies, simultaneously.ResultsRegarding the discovery study, principal component analysis identified the role of miR-181-family (miR-181a-5p, miR-181b-5p, miR-181c-5p) in clustering CNS-positive (CNS+) and CNS-negative (CNS‒) CSF samples. We were able to validate miR-181a expression differences: it was about 52 times higher in CSF samples of CNS+ ALL patients compared to CNS‒ cases (n = 8 vs. n = 10, ΔFC = 52.30, p = 1.5E-4), and CNS+ precursor B cell subgroup also had ninefold higher miR-181a levels in their BM (p = 0.04). The sensitivity of CSF miR-181a measurement in ALL highly exceeded those of conventional cytospin in the initial diagnosis of CNS leukemia (90% vs. 54.5%). Pellet resulting from ultracentrifugation of CNS+ CSF samples of ALL patients showed atypical CD63-/CD81- small EVs in high density by immunoelectron microscopy.ConclusionsAfter validating in extensive cohorts, quantification of miR-181a or a specific EV subtype might provide novel tools to monitor CNS disease course and further adjust CNS-directed therapy in pediatric ALL.

Project description: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.

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Pharmacogenetics of the Central Nervous System-Toxicity and Relapse Affecting the CNS in Pediatric Acute Lymphoblastic Leukemia.

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