Creation of a NGS-based classifier in adult T-ALL validated in pediatric T-ALL. (A-B) CIR (A) and OS (B) in 198 adult T-ALL (GRAALL03/05 protocols) by NFRP and NGS–based classifier status; 19 of 123 patients (15%) who would have previously been classified in LR based on their NFRP status joined the HR-NGS subgroup based on their PI3K (other than PTEN alterations), DNMT3A, TP53, IDH1/2, or IKZF1 status, and 4 of 75 patients (5%) who would have previously been classified in HR based on their NFRP status joined the LR-NGS subgroup based on their PHF6 or EP300 status. (C) In GRAALL03/05, CIR at 5 years was 21% (95% CI, 14-29) in LR-NGS patients (n = 108), compared with 47% (95% CI, 36-57) in HR-NGS patients (n = 90; P < .0001). (D) In GRAALL03/05, OS at 5 years was 83% (95% CI, 76-90) for LR-NGS patients, compared with 55% (95% CI, 45-66) for HR-NGS patients (P < .0001). (E-F) CIR (E) and OS (F) in 242 pediatric T-ALL (FRALLE2000T protocol) by NFRP classifier and NGS-based classifier status; 21 patients of 144 (15%) who would have previously been classified in LR based on their NFRP status joined the HR-NGS subgroup; and 3 patients of 98 (3%) who would have previously been classified in HR based on their NFRP status joined the LR-NGS subgroup. (G) In FRALLE2000T, CIR at 5 years was 17% (95% CI, 11-24) in LR-NGS patients (n = 126), compared with 35% (95% CI, 26-44) in HR-NGS patients (n = 116; P = .001). (H) In FRALLE2000T, OS at 5 years was 88% (95% CI, 83-94) in LR-NGS patients, compared with 69% (95% CI, 61-79) in HR-NGS patients (P = .0003).