Effect of Age and Weight on Toxicity and Survival in Pediatric Acute Myeloid Leukemia
Authors: Løhmann Ditte Juel Adolfsen , Abrahamson Jonas , Ha Shau Yin , Jónsson Ólafur G. , Koskenvuo Minna , Lausen Birgitte , Palle Josefine , Zeller Bernward , Hasle Henrik 
Published: October 2019

Abstract
Objective: The overall survival of pediatric acute myeloid leukemia (AML) has been around 70% on recent protocols, but the treatment causes severe toxicity. Age and body mass index (BMI) at diagnosis have been associated with outcome in AML. We investigated if toxicity and outcome were associated with age and BMI in the NOPHO-AML 2004 protocol (2004-2013).
Methods: We reviewed toxicities and follow-up information of NOPHO AML-2004 registered in the database, including all protocol patients from the Nordic countries and Hong Kong who completed first induction (n=318). For children 2 years or older BMI standard deviation (SD) for age and sex was calculated and categorized (underweight: <-2 SD (n=12), healthy weight: -2-1 SD (n=171), and overweight: >1 SD (n=56)) according to the World Health Organization. Toxicities were registered after each block until end of treatment, stem cell transplantation, relapse or death. The age and weight groups were compared using cox-regression for the cumulative incidence of toxicity and the overall (OS) and event-free (EFS) survival. All estimates of age as risk factor were sex and ethnicity adjusted and estimates of weight as risk factor sex, ethnicity and age adjusted (age stratified for the survival analysis).
Results: The cumulative incidence of treatment-related mortality was 4.6% (95%-CI 2.3-7.0%). Older children (10-17 years) were at higher risk of developing sepsis with hypotension (adjusted hazard ratio (HR) 2.3 (95%-CI 1.1-4.6) p=0.02) compared to children from 2-9 years.
Overweight children (compared to healthy weight) also had a higher risk of experiencing sepsis with hypotension (adjusted HR 2.1 (95%-CI 1.0-4.3) p=0.051) and severe abdominal pain (adjusted HR 1.7 (95%-CI 1.0-3.0), p=0.048).
The 5-year EFS and OS for the 318 patients were 50% (95%-CI 44-56%) and 71% (95%-CI 65-76%) respectively. Outcome depended on age. Infants (<1 year) had a trend for superior EFS when comparing to children from 2-9 years (adjusted HR 0.52, 95%-CI 0.26-1.02, p=0.06). EFS were similar for children from 2-9 years and 10-17 years. The older children showed a trend for inferior OS (adjusted HR 1.49, 95%-CI 0.90-2.45, p=0.12). Infants had similar OS as children from 2-9 years.
For children from 2-9 years overweight (BMI>1 SD for age) at diagnosis did not appear to be prognostic marker for EFS (adjusted HR 1.10, 95%-CI 0.55-2.16, p=0.80) or OS (adjusted HR 1.01, 95%-CI 0.35-2.93, p=0.99), but in children from 10-17 years there was a trend for overweight being a positive prognostic marker for EFS (figure 1) and OS (figure 2).
Conclusion: Older age and overweight was associated with increased toxicity during treatment for pediatric AML. Infants had superior EFS and older children had inferior OS compared to children from 2-9 years. In contrast to previous pediatric reports we found overweight at diagnosis was not a poor prognostic marker for survival, in contrast in older children there was a trend for overweight being a positive prognostic marker. These findings suggest different pharmacokinetics of chemotherapeutic drugs in adolescences compared to younger children and warrant further studies.

Disclosures
No relevant conflicts of interest to declare.