Induction Toxicities Are More Frequent in Young Adults Compared to Children Treated on the Children's Oncology Group (COG) First Relapse B-Lymphoblastic Leukemia Clinical Trial AALL1331
Authors: Hogan Laura Brook , Bhatla Teena , Rheingold Sue , Ji Lingyun , Xu Xinxin , Raetz Elizabeth A. , Hunger Stephen P. , Loh Mignon L. , Brown Patrick 
Published: October 2019

Abstract
Background
COG AALL1331 randomizes first relapse B-lymphoblastic leukemia (B-ALL) patients ages 1-30 years (yrs) to standard chemotherapy +/- blinatumomab after a common Induction (Block 1) based on the mitoxantrone arm of UKR3 ALL (Parker et al., 2010, n=103, age up to 18 years). Block 1 therapy consists of weekly vincristine, dexamethasone (days 1-5, and 15-19), pegaspargase (days 3 and 17), mitoxantrone (days 1,2) and intrathecal chemotherapy (based on CNS status) without blinatumomab.
Methods
We reviewed CTCAE4.0 grade 3-5 adverse events (AE) collected as per standard and expedited (AdEERS) reporting mechanisms during induction for all patients who completed Block 1 between December 2014 (study activation) and March 31, 2018. Cytopenias are universal and were excluded from reporting. For AE that occurred in greater than 5% of patients, we used Pearson's chi-squared tests to evaluate univariate associations between AE rates and age, sex, race/ethnicity, relapse site, peripheral blast count at relapse and duration of first remission (CR1).
Results
Block 1 reporting was completed in 405 patients, 194 aged 1-9 yrs, 165 aged 10-18 yrs, and 46 aged 19-30 yrs, with median age of 10 yrs and a range of 1 to 26 yrs (Table 1). Grade 3-5 AE that occurred in more than 5% of patients are listed in Table 2, and notable associations are summarized in Table 1. Sixteen patients died (4.0%); 15 from infection/sepsis, 1 death NOS. Grades 3-5 infection occurred in 161/405 (39.8%) of patients. By univariate analysis, total infections and sepsis were more common in young adults who were 19-30 yrs (incidence of infections: 37.1%, 38.2%, and 56.5% in patients 1-9 yrs, 10-18 yrs, and 19-30 yrs, respectively, p=0.047 overall, and p=0.014 for <19 vs. 19-30; incidence of sepsis: 7.2%, 9.7%, and 23.9%, p=0.003 overall, and p=0.001 for <19 vs. 19-30). Infections occurred more frequently in patients with marrow relapse (p=0.007), shorter CR1 duration (p<0.001), and higher peripheral blast count at relapse (p=0.001). Lower rates of sepsis were seen in patients who were African American, Asian or other races/ethnicities as compared to Hispanic/Latino or Caucasians (p=0.035 overall, and p=0.006 for African American/Asian/other vs. Latino/Caucasians). Oral mucositis, hyperbilirubinemia and hyperglycemia were also more common in young adults. Interestingly, both gastrointestinal disorders and hypoalbuminemia were seen more frequently in females. Thrombotic events were very rare, seen in only 0.49% of patients.
Conclusions
We have prospectively studied a large cohort that includes both children and young adult patients with first relapse of B-ALL treated with UKR3 ALL four drug induction. Infection is the most common AE and cause of death. Risk of infection was associated with older age (young adults) and other high risk relapse features (marrow involvement, short first remission, high peripheral blast count). Young adult patients were also at higher risk of several other toxicities, highlighting the importance of optimal supportive care in this population.

Disclosures
Rheingold: Pfizer: Research Funding.