Role of neurotrophic growth factors in vincristine polyneuropathy in children with acute lymphoblastic leukemia

Abstract

Vincristine-induced peripheral neuropathy (VIPN) is one of the frequent toxic complications in the treatment of acute lymphoblastic leukemia in children. The pathogenesis of peripheral nerve damage is not fully understood; however, recent studies have demonstrated the involvement of neurotrophic factors. The purpose of the study: to evaluate the level of plasma neurotrophic growth factors in children with acute lymphoblastic leukemia (ALL) and determine their association with the VIPN formation. Materials and methods: 131 newly diagnosed ALL patients aged 3 to 17 years receiving chemotherapy according to the ALL–MB 2015 protocol participated in a single-center prospective study. Depending on the development of VIPN, the patients were divided into two groups: the study group (n=106) — children with VIPN and the comparison group (n=25) — children without VIPN. The plasma level of neurotrophic growth factors (NGF-β and BDNF) was determined using multiparametric immunofluorescence analysis.Results: during the follow-up period, 80.9 % of the children (n=106) developed VIPN against the background of chemotherapy. In most cases, neurotoxic disorder manifested at the induction stage of treatment — in 84.9 % (n=90) of the patients. The clinical phenotype of VIPN was characterized by a combination of neurological disorders in 67.9 % (n=72) of the patients, with the predominance of sensory and motor symptoms. The comparative analysis of plasma neurotrophic growth factors in the groups of children with ALL depending on the VIPN formation showed that in the patients with VIPN, a statistically significant increase in brain-derived neurotrophic factor (BDNF) was noted at the consolidation stage of chemotherapy (study 1–284.3 (97.4÷628.3) pg/mL; study 2–281.7 (178.9÷679.2) pg/mL; study 3–980.2 (454.3÷2,005.9) pg/mL; p1-2=0.424 and p1-3=0.009). However, in the children without VIPN, an increase in this growth factor was observed during the induction phase (study 1–370.5 (95.4÷463.8) pg/mL; study 2–683.0 (362.4÷1,486.3) pg/mL; study 3–674.6 (394.8÷2,584.0) pg/mL; p1-2=0.043 and p1-3=0.021). In addition, in the study group patients with the early debut of VIPN, the level of nerve growth factor-β (NGF-β) before the administration of chemotherapy was significantly lower in contrast to the patients with its development in later terms (22.7 (10.9÷22.7) pg/mL and 24.7 (22.7÷91.5) pg/mL, respectively; p=0.045). When assessing the clinical value of this indicator, the diagnostic sensitivity was 88 %, specificity — 71 %, and the integral index characterizing the accuracy of the test was 0.81. Conclusion. The increase in plasma growth factor (BDNF) in earlier terms in children without VIPN probably reflects the mechanisms aimed at preventing the realization of VIPN. The established low concentration of plasma NGF-β and optimal diagnostic characteristics of the factor in children with early VIPN onset allow considering it as a prognostic biomarker.