Pediatric-inspired USC-ALL regimen vs hyper-CVAD in adults with Ph-negative and Ph-like acute lymphoblastic leukemia.

Adult acute lymphoblastic leukemia (ALL) outcomes remain inferior to pediatric results, motivating adoption of pediatric-inspired regimens (PIR) in adults. The optimal frontline regimen for high-risk subgroups, such as Philadelphia chromosome-like (Ph-like) ALL, has not been established. In this retrospective analysis, 160 adults with Philadelphia chromosome-negative B-cell or T-cell ALL treated between 2013 and 2024 received either the USC-ALL regimen, a pediatric-inspired protocol incorporating synchronized pegaspargase and high-dose methotrexate during two induction and six consolidation cycles followed by two years of POMP maintenance, or Hyper-CVAD. The cohort was predominantly Hispanic (77.2%) and 33.8% Ph-like, with median age 34 years and median follow-up 40.3 months. The USC-ALL regimen resulted in significantly higher rates of measurable residual disease (MRD) negativity by flow cytometry at complete remission (80.7% vs 50.0%, p = 0.002) and at the end of induction (79.5% vs 54.3%, p = 0.004). Three-year disease-free survival (DFS) favored USC-ALL (62.3% vs 36.7%; HR 2.15, p = 0.004), with a lower cumulative incidence of relapse (CIR; 34.3% vs 57.7%; HR 1.95, p = 0.019) and no difference in overall survival (OS). The DFS advantage remained significant in multivariate analysis adjusting for age, ALL subtype, and end-of-induction MRD status (HR 1.84, p = 0.031). The benefits were most pronounced in patients younger than 40 years and with Ph-like disease, where USC-ALL improved 3-year OS (89.8% vs 59.3%), DFS (65.3% vs 22.0%), and CIR (30.4% vs 68.4%). Pegaspargase toxicities were consistent with previous PIR experience. These results support pediatric-inspired, asparaginase-based regimens as preferred frontline therapy in adult ALL, particularly for Ph-like disease.