Kaplan-Meier estimates of RFS based on the gene expression classifier for RFS modeled on high-risk ALL cases lacking known recurring cytogenetic abnormalities and end-induction (day 29) MRD. (A) The second gene expression classifier modeled only on those high-risk ALL cases (n = 163; supplemental Table 8) from the COG 9906 ALL cohort lacking recurring cytogenetic abnormalities resolves 2 distinct risk groups of patients with significantly different RFS. (B) Day 29 flow MRD status separated these 163 ALL cases into 2 groups with significantly different RFS. (C-D) After dividing patients by their end-induction flow MRD status, an independent effect of the gene expression classifier for RFS is observed among both the flow MRD-negative (< 0.01% blasts; C) and flow MRD-positive (> 0.01% blasts; D) patients. (E-F) Combining the risk scores determined from the gene expression classifier and flow MRD yields 4 distinct outcome groups (E); the 2 discordant groups show no significant difference in RFS and are therefore collapsed into an intermediate-risk group for RFS prediction (F). (F) The hazard ratios (HR) and corresponding P values are based on the Cox regression (high-risk vs intermediate-risk, HR = 2.26, P = .007; intermediate-risk vs low-risk, HR = 2.77, P = .008). The P value reported in the lower left corner corresponds to the test for differences among all groups.