Pediatric-inspired USC ALL regimen vs hyper-CVAD in adults with ph-negative ALL: Real-world outcomes including blinatumomab in a predominantly hispanic cohort.

Abstract Introduction: Pediatric-inspired regimens have improved outcomes in adolescents and young adults with acute lymphoblastic leukemia (ALL), but the optimal frontline therapy for adults remains debated. The USC ALL regimen, a modified pediatric-based protocol with detailed composition established in prior institutional studies, incorporates PEG-asparaginase and multi-agent chemotherapy delivered sequentially across induction, consolidation, and maintenance phases. We retrospectively compared clinical outcomes and toxicities of USC ALL versus Hyper-CVAD in adult patients with newly diagnosed, Philadelphia chromosome (Ph)-negative ALL at our institution. Methods: This retrospective chart review included adults with newly diagnosed ALL treated with either Hyper-CVAD or USC ALL regimens at Norris Comprehensive Cancer Center (NCCC) between 2015 and 2024. The study was approved by the Institutional Review Board at the University of Southern California and conducted by the Declaration of Helsinki. Of 285 eligible patients (n=222 USC ALL, n=63 Hyper-CVAD), those with Ph-positive ALL (n=99) and those who did not receive PEG-asparaginase during either induction cycle (n=44) were excluded, leaving 158 patients for comparison. Demographic and clinical features were compared using Fisher's exact test for categorical variables and the Wilcoxon rank-sum test for continuous variables. Cumulative incidence of relapse (CIR) was assessed using competing risk regression (Fine-Gray method), with death as a competing outcome. Overall survival (OS) and disease-free survival (DFS) were analyzed using Cox proportional hazards models, with relapse and death as events for DFS. Patients treated with USC ALL served as the reference group. Results: Our predominantly Hispanic (75%) cohort (median age 35.5, range: 18-70) had a median follow-up of 43 months. Many patients were transplanted (n=83, 52.5%) and received blinatumomab (n=69, 44.8%) for measurable residual disease (MRD) or relapse. Most patients had Ph-negative B-ALL (n=89, 56.3%), followed by Ph-like B-ALL (n=50, 31.6%), T-ALL (n=18, 11.4%), and MPAL (n=1, 0.6%). Compared to those receiving Hyper-CVAD (n=43, 27.2%), patients given USC ALL (n=115, 72.8%) were younger (33 vs 44 years, P=0.036). While complete remission rates were similar, USC ALL patients were more often MRD-negative at CR (79.1% vs 56.7%, P=0.029). There were no differences in cytogenetics, sex, race/ethnicity, ALL/Ph subtype, CBC parameters, extramedullary disease, or refractory disease between groups. Within the USC ALL cohort, most patients received PEG during both induction cycles (n=84, 73.0%), with more receiving it in cycle 1 (n=108, 94.0%) than cycle 2 (n=91, 82.7%). The primary reason for withholding PEG in either cycle was transient hepatic dysfunction. The most common grade 3 or higher toxicities were hypofibrinogenemia (43.6%), febrile neutropenia (42.7%), elevated transaminases (18%), hyperbilirubinemia (13%), and thrombotic events (2.9%). For the entire cohort, 3-year OS, DFS, and CIR were 82.6% (95% CI: 75.9–89.9), 54.5% (95% CI: 46.4–64.0), and 42.4% (95% CI: 33.6–50.9), respectively. On univariate analysis, compared to USC ALL, Hyper-CVAD was associated with inferior DFS (3-year: 39.1% vs 61.0%; HR=2.00, 95% CI: 1.21–3.30, P=0.007) and increased CIR (56.0% vs 36.6%; HR=1.80, 95% CI: 1.07–3.05, P=0.028), but similar OS (76.2% vs 84.8%; HR=1.41, 95% CI: 0.63–3.16, P=0.40). After controlling for age, sex, and ALL/Ph type, Hyper-CVAD remained associated with significantly lower DFS (HR=2.06, 95% CI: 1.23–3.43, P=0.006) and higher CIR (HR=1.91, 95% CI: 1.07–3.35, P=0.023). In subgroup analyses by age (<40 vs ≥40), the younger cohort demonstrated persistently lower DFS (HR=2.56, 95% CI: 1.29–5.05, P=0.007) and higher CIR (HR=2.31, 95% CI: 1.17–4.58, P=0.016) with Hyper-CVAD relative to USC ALL, while outcomes were similar with both regimens in patients aged ≥40. Similar patterns were observed in Ph-like ALL: DFS (HR=2.94, 95% CI: 1.27–6.80, P=0.012), CIR (HR=2.91, 95% CI: 1.27–6.67, P=0.012), and no difference in OS (HR=3.54, 95% CI: 0.79–15.9, P=0.10). Conclusions: USC ALL was associated with improved disease-free survival and lower relapse compared to Hyper-CVAD in adults with Ph-negative ALL, particularly in patients under 40 and those with Ph-like disease. These findings support pediatric-inspired regimens as a preferred frontline regimen for select adult populations.