Vincristine-Induced Neuropathy in UKALL 2011: Effects of Vincristine/Dexamethasone Pulse Omission and Prospective Gait Outcomes

PURPOSE Vincristine-induced peripheral neuropathy (VIPN) is a frequent, disabling complication of ALL therapy, yet its trajectory and risk factors remain incompletely defined. We prospectively evaluated VIPN, focusing on the impact of omitting vincristine/dexamethasone maintenance pulses and the utility of gait analysis as a functional end point. METHODS This substudy was embedded within UKALL 2011. In all, 96 participants were enrolled; of these, 67 completed sufficient longitudinal neuropathy assessments without relapse and were included in the primary analyses, and 39 were randomly assigned to maintenance vincristine/dexamethasone pulses or no pulses. Participants age ≥5 years underwent Total Neuropathy Score–Pediatric Vincristine Revised (TNS-PVr) assessments at predefined time points from baseline to end-of-treatment. In addition, 46 participants underwent gait analysis using the GAITRite walkway, standardized to age- and sex-matched norms. Mixed-effects models estimated incidence rate ratios (IRRs) for neuropathy burden and explored pharmacogenomic associations. RESULTS VIPN peaked after delayed intensification (51% with clinically significant neuropathy; TNS-PVr ≥5), improved during maintenance, and persisted in 16% at therapy completion. Gait analysis showed significantly reduced velocity, cadence, and step length versus norms (step length, –0.95 [95% CI, –1.14 to −0.76]; P < .001), with only partial recovery. Neuropathy burden increased with more-intensive vincristine therapy (IRR, 2.18 [95% CI, 1.07 to 4.42]; P = .032) and was reduced by omission of vincristine/dexamethasone pulses (IRR, 1.39 [95% CI, 1.06 to 1.84]; P = .019). Pharmacokinetics showed wide variability but no relationship to neuropathy. Pharmacogenomics revealed modest associations between neuropathy and single nucleotide polymorphisms associated with ABCB1 and SNU13 genes. CONCLUSION VIPN is common, peaks during intensive phases, and persists in a minority at therapy completion. Our results provide randomized evidence that pulse omission reduces neuropathy burden, whereas gait analysis offers an objective end point to guide future ALL protocols and survivorship assessment.