Increased Toxicity Among Adolescents and Young Adults Treated for Acute Myeloid Leukemia at US Children's Hospitals
Authors: Sinno Mohamad G. , Butala Sneha , Dalal Jignesh 
Published: February 2020

Introduction
Adolescents and Young Adults (AYAs) with cancer are known to experience disparities in access to care along with delays in diagnosis and treatment. Acute Myeloid leukemia (AML) represents 15-20% of childhood leukemias and 33% of adolescent leukemias. Although improvements in the survival of pediatric AML is encouraging, older age has historically been an adverse prognostic factor, and survival does not appear to be improving to the same extent in AYAs as in children. AYA patients treated on pediatric trials had better outcomes than those treated on adult trials. As a result, AYAs are increasingly being treated in children's hospitals on pediatric protocols, which generally consist of intensified regimens compared with adult protocols. However, minimal data exists regarding how well AYAs tolerate the intensity of chemotherapy at doses and regimens designed for children. Our study aims to compare toxicities between pediatric and AYA patients treated for AML in children's hospitals in the United States.
Methods
With IRB approval, the Pediatric Health Information Systems (PHIS) database was queried to analyze healthcare outcomes in pediatric and AYA patients with AML admitted between January 2004 and December 2018. We chose to utilize the PHIS database, as these AYA patients with AML were more likely to have been treated on pediatric protocols. AYA was defined as patients between the ages of 15 and 39 per the National Cancer Institute (NCI) definition. We extracted relevant ICD-9 and -10 diagnoses, procedure codes and medications for each patient related to toxicities as outlined by the NCI.
For the descriptive statistics, demographics and clinical characteristics of patients were described using median and interquartile ranges for continuous variables, and frequency and percentages for categorical variables. Categorical variables were analyzed with the chi-square test. Continuous variables were assessed by the Mann Whitney U test. Multiple logistic regression was performed with 'discharge mortality' as the primary outcome. The age was categorized into two levels (0-14 y.o and ≥ 15 y.o). P-value of less than 0.05 or absence of 1 in the 95% confidence intervals were considered as statistically significant for the analysis. All statistical analyses were performed using SAS software, version 9.4 (SAS institute, Cary, NC).
Results
A total of 31,868 admissions met inclusion criteria, representing a total of 7,229 AML patients. Of these, 8,606 admissions (27%) were in the AYA group. 64% of children and 67% of AYA patients were Caucasians. AYA patients had a significantly higher incidence of ICU stay [20.1% vs 15.7%, p&lt;0.0001] and overall mortality [23.4% vs 15.5%, p&lt;0.0001]. Out of a total of 7,229 AML patients, 1277 (18%) passed away. Table 1 describes our findings and show statistically significant differences among the two groups, with AYA patients showing markedly increased toxicity, and requiring more supportive medications and procedural interventions. No difference in terms of need for blood and platelets products was observed among the two groups. 24.4% of children and 31.6% of AYA patients underwent stem cell transplant. We identified no significant differences in mortality between these two groups. After adjusting for other factors, diagnosis prior to 2014, public insurance, African American ethnicity in ≥ 15 y.o, ICU stay and use of antifungals other than fluconazole, were associated with inferior outcome. ICU stay remained the strongest predictor of mortality (OR 10.5, 95% CI = 8.85 - 12.47 for pediatric patients, and OR 13.3, 95% CI = 10.39 - 17.03 for AYA patients).
Conclusion
To our knowledge, this is the largest multicenter database study evaluating toxicity and mortality in AML patients. Compared to children, AYA patients developed disproportionately higher toxicities from chemotherapy and required more supportive medications and procedures. We found overall increased mortality in AYA patients, however the negative impact of older age lost its significance in an additional analysis focusing on transplant patients. Despite improvements in treatments and outcomes over time, there is still need for more effective strategies for preventing toxicities and mortality in AYA patients. Prospective studies are needed to assess whether dose modifications for certain chemotherapeutics may improve the toxicity profile of AYA patients with AML treated in Children's hospitals.

Disclosures
No relevant conflicts of interest to declare.