Sex-Based Disparities in Outcome in Childhood Acute Lymphoblastic Leukemia (ALL): A Children's Oncology Group (COG) Report
Authors: Gupta Sumit , Teachey David T. , Devidas Meenakshi , Chen Zhiguo , Dunsmore Kimberly P. , Larsen Eric C , Maloney Kelly , Mattano Leonard A. , Winter Stuart S. , Carroll Andrew J , Heerema Nyla A , Borowitz Michael J , Wood Brent L , Carroll William L. , Winick Naomi J , Raetz Elizabeth A. , Loh Mignon L. , Hunger Stephen P. 
Published: February 2021

BACKGROUND: Survival for children with B and T acute lymphoblastic leukemia (B-ALL, T-ALL) has continued to improve. In past cohorts, boys experienced inferior survival outcomes compared to girls. Though reasons are unknown, previous investigators have suggested that these disparities are explained by imbalances in risk factors, such as a higher proportion of T-ALL among boys. We thus examined whether sex-based disparities persist with modern intensive therapy when adjusted for other risk factors. We also determined if patterns of toxicity and treatment failure varied by sex.
METHODS: We identified a cohort of patients age 1-30.99 years enrolled on frontline COG trials for B-ALL (standard risk: AALL0331; high risk: AALL0232) and T-ALL (AALL0434) between 2004-2014. Duration of treatment was sex-dependent, with boys receiving an additional year of Maintenance therapy. A limited number of B-ALL patients (those with slow early response or CNS3 status) underwent cranial radiation, while all intermediate and standard risk T-ALL patients did so. Sex-based differences in the distribution of various prognostic factors were explored, including age at diagnosis, initial white blood cell (WBC) count, central nervous system (CNS) status, leukemia cytogenetics, and end Induction minimal residual disease (MRD). Event-free and overall survival (EFS, OS) were compared between boys and girls using log-rank tests and multivariable Cox regression analyses. Finally, we explored sex-based differences in toxicity rates and in the cumulative incidence of specific causes of treatment failure, including treatment-related mortality (TRM), overall relapse, and subcategories of relapse by site.
RESULTS: The study cohort included 8,202 patients with B-ALL [4,463 (54.4%) boys] and 1,562 patients with T-ALL [1,161 (74.3%) boys]. Among B-ALL patients, boys were older than girls and slightly more likely to have unfavorable cytogenetics (Table 1). There was no difference in the distribution of initial WBC or CNS status. Among T-ALL patients, boys were again older than girls, but other prognostic factors did not differ by sex (Table 1). B-ALL boys were less likely to be end induction marrow MRD &lt; 0.01% [3,268 (76.1%) vs. 2791 (78.1%); p=0.04] while T-ALL boys were more likely to achieve end induction MRD &lt; 0.01% [659 (59.0%) vs. 221 (56.8%); p=0.01], although in both cases absolute differences were small.
EFS and OS were inferior in B-ALL boys compared to girls (5-year: EFS 84.6%±0.6% vs. 86.4%±0.6%; p=0.003; OS 91.7%±0.4% vs. 92.8%±0.5%; p=0.046). The risk of inferior outcomes among B-ALL boys persisted after adjustment for other prognostic factors in both EFS [hazard ratio (HR) 1.18, 95% confidence interval (1.05-1.33); p=0.003] and OS (HR 1.17 (1.00-1.37); p=0.048). There were no sex-based differences in EFS or OS in T-ALL.
When examining specific toxicities and causes of treatment failure, osteonecrosis rates were lower among boys [297/5,624 (5.3%) vs. 281/4,140 (6.8%); p=0.002]. The incidence of TRM did not differ by sex. The incidence of relapse was, however, greater in boys than girls with B-ALL (11.2%±0.5% vs. 9.6%±0.5%; p=0.001). This risk was attributable to a higher incidence of relapses involving the CNS (4.2%±0.3% vs. 2.5%±0.3%; p&lt;0.0001) and in other extramedullary sites, including the testes (1.3%±0.2% vs. 0.7%±0.1%; p= 0.001). Notably, there was no difference in the cumulative incidence of isolated bone marrow relapse (5.4%±0.4% vs. 6.2%±0.4%; p=0.49). Among T-ALL patients, there were no sex-based differences in the cumulative incidence of relapse, either overall or by relapse site.
CONCLUSIONS: Small sex-based disparities in ALL outcomes persist despite overall improvements, extended treatment duration, and extra intrathecal therapy in boys. This is mainly attributable to a higher risk of CNS relapse in boys with B-ALL, despite no sex-based differences in initial CNS status, and persists when adjusted for other prognostic risk factors. The lack of sex-based disparities in T-ALL by sex may be in part due to an increased use of CNS radiation, given older studies which observed increases in CNS relapse rates among boys but not girls when radiation was eliminated. Future studies to determine the mechanisms underlying this disparity, including potential sex-based differences in steroid metabolism, are warranted.

Disclosures
Teachey: Amgen: Consultancy; Sobi: Consultancy; Janssen: Consultancy; La Roche: Consultancy. Dunsmore:Dexcom: Current equity holder in publicly-traded company. Mattano:Melinta Therapeutics: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Borowitz:Amgen: Honoraria. Raetz:Pfizer: Research Funding; Celgene/BMS: Other. Loh:Pfizer: Other: Institutional Research Funding; Medisix Therapeutics: Membership on an entity's Board of Directors or advisory committees. Hunger:Novartis: Consultancy; Amgen Inc.: Current equity holder in publicly-traded company, Honoraria.