Body mass index during maintenance therapy and relapse risk in children with acute lymphoblastic leukemia: A Children's Oncology Group report

Abstract

Background: Obesity at diagnosis of childhood acute lymphoblastic leukemia (ALL) is associated with greater risk of relapse; whether this association extends to obesity during maintenance is unstudied.

Methods: This study used data from AALL03N1 to calculate median body mass index (BMI) for 676 children over 6 consecutive months during maintenance therapy; BMI percentile (BMI%ile) were operationalized as normal/underweight (<85%ile), overweight/obese (85%-98%ile), and extreme obesity (≥99%ile). Hazard of relapse was estimated using multivariable proportional subdistributional hazards regression after adjusting for all relevant demographic and clinical predictors.

Results: Median age at study enrollment was 6 years and median length of follow-up was 7.9 years. Overall, 43.3% of the cohort was underweight/normal weight, 44.8% was overweight/obese, and 11.8% had extreme obesity. Cumulative incidence of relapse at 4 years from study enrollment was higher among those with extreme obesity (13.6% ± 4.5%) compared to those with underweight/normal weight (9.0% ± 2.1%). Multivariable analysis revealed that children with extreme obesity had a 2.4-fold (95% confidence interval [CI], 1.1-5.0; p = .01) greater hazard of relapse compared to those who were underweight/normal weight. Overweight/obese patients were at comparable risk to those who were underweight/normal weight (hazard ratio, 0.8; 95% CI, 0.4-1.6). Erythrocyte thioguanine nucleotide (TGN) levels were significantly lower among children with extreme obesity compared to those with underweight/normal weight (141.6 vs. 168.8 pmol/8 × 10⁸ erythrocytes; p = .0002), however, the difference in TGN levels did not explain the greater hazard of relapse among those with extreme obesity.

Conclusions: Extreme obesity during maintenance therapy is associated with greater hazard of relapse in children with ALL. Underlying mechanisms of this association needs further investigation.

Lay summary: Findings from this study demonstrate that extreme obesity during maintenance therapy is associated with a greater hazard of relapse among children with acute lymphoblastic leukemia. We show that children with obesity have lower levels of erythrocyte thioguanine nucleotides even after adjusting for adherence to oral chemotherapy. However, these lower levels do not explain the greater hazard of relapse, paving the way for future studies to explore this association.

Keywords: child; drug metabolites; leukemia; obesity; recurrence.