Bone mineral density in children with acute lymphoblastic leukemia

Abstract

Background: Children with acute lymphoblastic leukemia (ALL) can develop reduced bone mineral density (BMD). However, data from patients who received treatment on a frontline regimen without cranial irradiation are limited, and no genome-wide analysis has been reported.

Methods: Lumbar BMD was evaluated by quantitative computed tomography at diagnosis, after 120 weeks of continuation therapy, and after 2 years off therapy in pediatric patients with ALL (ages 2-18 years at diagnosis) who were treated on the St. Jude Total XV Protocol. Clinical, pharmacokinetic, and genetic risk factors associated with decreased BMD Z-scores were evaluated.

Results: The median BMD Z-score in 363 patients was 0.06 at diagnosis, declined to -1.08 at week 120, but partly recovered to -0.72 after 2 years off therapy; BMD in patients with low BMD Z-scores at diagnosis remained low after therapy. Older age (≥10 years vs 2-9.9 years at diagnosis; P < .001), a higher BMD Z-score at diagnosis (P = .001), and a greater area under the plasma drug concentration-time curve for dexamethasone in weeks 7 and 8 of continuation therapy (P = .001) were associated with a greater decrease in BMD Z-score from diagnosis to week 120. Single-nucleotide polymorphisms in 2 genes important in osteogenesis and bone mineralization (COL11A1 [reference single-nucleotide polymorphism rs2622849]; P = 2.39 × 10^-7 ] and NELL1 [rs11025915]; P = 4.07 × 10^-6 ]) were associated with a decreased BMD Z-score. NELL1 (P = .003) also was associated with a greater dexamethasone area under the plasma drug concentration-time curve.

Conclusions: BMD Z-scores decreased during therapy, especially in patients who had clinical, pharmacokinetic, and genetic risk factors. Early recognition of BMD changes and strategies to optimize bone health are essential. Cancer 2018;124:1025-35. © 2017 American Cancer Society.

Keywords: acute lymphoblastic leukemia; bone mineral density; chemotherapy; children; single-nucleotide polymorphism.

Figure 1. CONSORT diagram

Abbreviations: BMD, bone mineral density; HSCT, hematopoietic stem cell transplant

Figure 2. Single-nucleotide polymorphisms that are associated with bone mineral density (BMD) Z-score changes from diagnosis to week 120 of continuation therapy

Data are adjusted for age at diagnosis, treatment risk, BMD Z-scores at diagnosis, and ancestry group. Manhattan plots (A) and box plots (B and C) for COL11A1 and NELL1 are shown.