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Vincristine toxicity with co‐administration of fluconazole: Long‐term concerns

To the Editor: I thank Smitherman et al.1 for their recent article in Pediatric Blood and Cancer, which was a retrospective review comparing rates of vincristine-related toxicities associated with fluconazole exposure during induction therapy in pediatric patients with acute lymphoblastic leukemia (ALL). Fluconazole is a moderate cytochrome P450 3A4 inhibitor and vincristine is extensively metabolized in the liver via cytochrome P450 3A4; thus, there is concern for increased vincristine toxicity in patients receiving co-administration of fluconazole. Research regarding the clinical implication of this drug–drug interaction has not settled the debate and current clinical practice tends to vary based on the treatingmedical team.1,2 Smitherman et al.1 concluded the co-administration of fluconazole during induction therapy for pediatric ALL does not significantly increase the risk for vincristine-associated toxicities. Concerns regarding the limited number of vincristine doses, duration of patient assessment, and absence of reported rates of fungal infections jeopardize the external validity and clinical implication of the trial’s findings. First, the authors rightly point out that accumulating doses of vincristine play a role in the development of chemotherapy-induced peripheral neuropathy (CIPN), which is substantiated in survivorship literature.3–5 Induction chemotherapy includes 3–4 vincristine doses (4.5–6 mg/m2), whereas a typical ALL regimen (based on protocol and risk status) includes approximately 40–50 vincristine doses for a cumulative dose (60–75 mg/m2).6,7 Limiting the study to the induction phase only does not address the larger concern of long-term neurotoxicity. Second, the prevalence of CIPNhas been noted to peak 2–4months after beginning therapy and recent findings suggest that vincristineinduced peripheral neuropathy should be recognized as a late effect of chemotherapy4,8 Smitherman et al.1 assessed toxicity during the first 6weeks of therapy, which is a probably too short of a time frame to see any significant toxicities or dose reductions of vincristine thatwould be due to the concomitant administration of fluconazole. Finally, the authors state their primary concern for toxicity of this drug–drug interaction was during induction therapy due to the high risk of fungal infections in that phase of therapy. However, rates of fungal outcomes were not reported for the cohort or compared between the two groups. CIPN is one of the most important dose-limiting toxicities that may result from cumulative doses of vincristine and can have long-term effects on physical function and quality of life for childhood