A decrease in vitamin D levels is associated with methotrexate-induced oral mucositis in children with acute lymphoblastic leukemia

Abstract

Purpose: Children with acute lymphoblastic leukemia (ALL) are at increased risk of vitamin D deficiency, which might make them more susceptible to developing adverse events. Previous studies showed that low vitamin D levels were associated with an increased inflammatory mucosal state and impaired mucosal tissue barriers. We examined the prevalence of vitamin D deficiency and studied the association between vitamin D levels and methotrexate (MTX)-induced oral mucositis in pediatric ALL.

Methods: We assessed 25-hydroxyvitamin D (25(OH)D₃) and 24,25-dihydroxyvitamin D (24,25(OH)₂D₃) levels in 99 children with ALL before the start of 4 × 5 g/m² high-dose methotrexate (HD-MTX) (T0) and in 81/99 children after discontinuation of HD-MTX (T1). Two cutoff values for vitamin D deficiency exist: 25(OH)D₃ levels < 30 and < 50 nmol/L. Oral mucositis was defined as grade ≥ 3 according to the National Cancer Institute Criteria.

Results: Vitamin D deficiency occurred in respectively 8% (< 30 nmol/L) and 33% (< 50 nmol/L) of the patients at T0, and more frequently in children > 4 years of age as compared to children between 1 and 4 years of age. A decrease in 25(OH)D₃ levels during HD-MTX therapy was associated with developing severe oral mucositis (OR 1.6; 95% CI [1.1-2.4]). 25(OH)D₃ and 24,25(OH)₂D₃ levels at T0 and the change in 24,25(OH)₂D₃ levels during therapy were not associated with the development of severe oral mucositis.

Conclusions: This study showed that vitamin D deficiency occurs frequently in pediatric ALL patients above the age of 4 years. A decrease in 25(OH)D₃ levels during MTX therapy was observed in children with ALL that developed severe oral mucositis.

Keywords: Acute lymphoblastic leukemia; Methotrexate; Oral mucositis; Vitamin D.

Fig. 1

Flowchart of patient inclusion. ALL, acute lymphoblastic leukemia; HD-MTX, high-dose methotrexate; DCOG, Dutch Childhood Oncology Group; SNP, single-nucleotide polymorphism; n, number of patients; * one patient had neurological damage before the start of HD-MTX treatment, one patients was transferred to another hospital, one patient had an adjusted protocol due to a SPINKS mutation, and one patient was initially treated otherwise due to another diagnosis

Fig. 2

25(OH)D₃ levels at T0 and T0 in relation to the development of oral mucositis. 25(OH)D₃ levels at T0 and T1 in individual patients with (yes, n = 62) and without (no, n = 19) mucositis; the red lines indicate the mean 25(OH)D₃ levels at T0 and T1 of all patients; the blue lines indicate the 95% confidence interval; the dotted line indicates the cutoff value of vitamin D deficiency at 25(OH)D₃ levels < 50 nmol/L.