Impact of age and sex on survival outcomes in patients aged 1-45 years with acute lymphoblastic leukemia treated according to the stratification used in the NOPHO ALL2008 trial

Age and sex have historically been associated with differences in the survival of patients with acute lymphoblastic leukemia (ALL). The NOPHO ALL2008 trial included patients aged 1-45 years with BCR::ABL1-negative B-precursor and T-cell ALL, but neither sex nor age was integrated into risk group allocation. Among 1,771 trial patients stratified into protocol- appropriate risk groups, we estimated the impact of age and sex on survival (even after relapse) and toxicities prospectively registered at 3-month intervals. In multivariate Cox regression analysis adjusted by sex, age group, and risk group, age but not sex was an independent risk factor for reduced 5-year event-free survival (EFS): hazard ratio=1.57 (95% confidence interval: 1.15-2.14) for patients 10-17.9 years, and 2.70 (95% confidence interval: 2.03-3.58) for patients 18-45 years, compared to patients <10 years old at diagnosis. The overall 5-year pEFS was 0.83. For standard-risk patients (B-lineage, white cell count <100x109/L, no risk genetics, minimal residual disease day 29 <0.1%), an inferior 5-year EFS was observed among patients 18-45 years (pEFS 0.78, P<0.001) and 10-17.9 years (pEFS 0.86, P=0.002) compared to patients <10 years at diagnosis (pEFS 0.93). For the intermediate-risk and high-risk groups, EFS was worse for patients 18-45 years compared to patients <10 years: pEFS 0.69 versus 0.89 (P<0.001) and pEFS 0.55 versus 0.71 (P=0.005), respectively. Osteonecrosis and veno-occlusive disease were associated with female sex in the standard-risk group, and age ≥10 years was associated with osteonecrosis, thrombosis, and pancreatitis in sex- and treatment-group-adjusted analyses. In conclusion, this study indicates that risk-grouping and/or treatment-intensity criteria should differ across age groups and that age-adapted strategies to mitigate toxicities are needed.