An updated strategy combining pediatric-based chemotherapy with risk-oriented allogeneic hematopoietic cell transplantation (HCT) was evaluated in Philadelphia chromosome-negative acute lymphoblastic leukemia (Ph- ALL) and compared with a published control series. Following induction-consolidation chemotherapy, responsive patients were assigned to receive maintenance chemotherapy or undergo early HCT according to the risk stratification criteria and minimal residual disease (MRD) status. Of the 203 study patients (median age 41 years, range 17-67), 140/161 with Ph- ALL achieved complete remission (86.9%; 91.6% ≤55 years, P = 0.0002), with complete MRD clearing in 68/109; 55 patients were assigned to maintenance chemotherapy, and 85 to HCT due to very high-risk characteristics (hyperleukocytosis, adverse genetics, early/mature T-precursor ALL, and MRD persistence). The 5-year relapse incidence was 36%, and the treatment-related mortality rate was 18%. Median overall and relapse-free survival were 7.4 and 6.2 years, with rates of 54 and 53% at 5 years, respectively, which were significantly better than those obtained with the historical protocol (P = 0.001 and P = 0.005, respectively), without significant differences between maintenance and HCT cohorts. In prognostic analysis, MRD negativity and age ≤55 years were the most favorable independent prognostic factors. A reduction in treatment toxicity and further improvements in the risk definitions and risk-oriented design are the focuses of this ongoing research.