CIPN is a relatively common complication in children and adolescents undergoing treatment for ALL and it is mostly associated with the use of neurotoxic agents as vinca alkaloids. The incidence of CIPN varies from 20% to 60% based on its degrees and is characterized by a large spectrum and severity of symptoms that negatively impact the quality of life and may require significant treatment delays or dose reduction. Despite its clinical relevance, there are still no standardized methods to define CIPN or reliable markers for early detection of severe CIPN. NfL has been recently identified as specific blood markers of the severity of axonal damage and can be measured in the blood, but there are no data available in the literature regarding NfL in the pediatric population with ALL.

A prospective low-interventional clinical study to determine the incidence of CIPN and the variation of serum NfL concentrations at specific timepoints (T) was conducted in pediatric patients (age 1-17 years) with newly diagnosed ALL treated at our Pediatric Hematology-Oncology Unit according to the AIEOP-BFM ALL 2017 protocol. Patients received a 4-drug induction therapy, including 5 weeks of steroids, 4 weekly doses of vincristine (VCR, 1.5 mg/sqm, max dose 2 mg) and daunorubicin on days 8, 15, 22 and 29, 2 doses of PEG-L-Asparaginase and 3 intrathecal doses of methotrexate. Timepoints were scheduled at diagnosis (T0), after 3 and 5 weeks (T1, day 22 and T2, day 33). At each timepoint, patients were tested for serum NfL level and underwent a thorough neurologic evaluation by the same physician (GAK). In patients aged ≥3, the incidence and severity of CIPN was assessed through the pediatric-modified Total Neuropathy Scale (ped-mTNS) and classified as mild (score 0-4), moderate (score 5-9) and severe (score ≥10). Serum NfL was measured with Fujirebio CLEIA technology by a one-step sandwich immunoassay method.

From February 2024 to May 2025, 30 patients were enrolled in the study. Characteristics at diagnosis were male sex in 60%, median age of 10.5 years (with 7 patients being <3 years old), B-cell immunophenotype in 80%, WBC≥100×109/L in 16.7% and CNS involvement in 4.3% of patients.

At T0, the median level of serum NfL was 8.8 pg/ml (IQR 6.1-15.4) and baseline values were similar throughout all patients' groups depending on gender, age, immunophenotype, WBC and CNS status. After the start of chemotherapy, an increase of median NfL levels to 57.3 pg/ml (38.2-130.5) at T1 and to 120.3 pg/ml (72.0-201.3) at T2 was seen. Interestingly, patients aged 1-9 had a higher median NfL level at T1 compared to older patients but not at T2. In addition, different patterns of NfL increase during induction were observed in patients who had a greater increase of NfL levels from T0 to T1 than between T1 and T2: they were mostly younger (78.6% aged 1-9 years), whilst those with a greater increase between T1 and T2 were mostly older than 10 years (80%).

The evaluation of CIPN showed that at baseline (T0), no patients presented with any grade of neuropathy. At T1, moderate neuropathy was observed in 34.8% of patients, with a median score of 4.0 (IQR 3.0-5.0). At T2, 62.5% of patients had clinically relevant neuropathy, being moderate in 45.8% and severe in 16.7%, with a median score of 6.0 (IQR 4.0-7.2). Patients aged ≥10 years were more commonly affected by neuropathy compared to younger patients at T1 (50% vs 11.1%) and at T2 (73.3% vs 44.4%).

Finally, the relationship between NfL levels and the severity of CIPN was explored. We found no relevant differences in median NfL levels between patients with mild neuropathy compared to those with moderate at T1 (53.2 vs 45.1 pg/ml) and at T2 (120.3 vs 82.5 pg/ml). However, higher levels were found in patients with severe neuropathy at T2 (median 233.2 pg/ml).

This is the first study showing that NfL levels increase in the serum of pediatric patients undergoing induction treatment for ALL consisting also of neurotoxic agents. Younger patients were more likely to present with earlier increase of NfL levels compared to older patients, who, conversely, had a greater incidence of CIPN. Despite the cohort is still limited, our findings indicate a correlation between NfL levels and severe neuropathy, providing a rationale for additional studies on NfL as biomarkers of CIPN in pediatric patients with ALL.

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2025
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