Effectiveness and prognostic impact of BMI, MRD and CNS involvement in AYA patients with Philadelphia-negative ALL treated using the AYA-15 protocol: Real-world from a tertiary center in the middle east

Abstract Background Pediatric-inspired chemotherapy regimens have improved outcomes in adolescents and young adults (AYA) with acute lymphoblastic leukemia (ALL). However, real-world evidence from non-Western regions remains limited. We evaluated the effectiveness and tolerability of the AYA-15 protocol in AYA patients with Philadelphia-negative (Ph–) ALL treated at a tertiary care center in the Middle East. Methods We retrospectively analyzed 149 consecutive AYA patients (median age 18 years, range 14–51) diagnosed with Ph– B- or T-ALL between 2015–2024 and treated with the AYA-15 protocol. MRD was assessed by 8-color flow cytometry post-induction and post-consolidation. Endpoints included overall survival (OS), disease-free survival (DFS), and event-free survival (EFS). Prognostic factors were identified by multivariable Cox regression. Toxicities were graded per CTCAE v5.0. Results Among the 149 patients, 74% had B-ALL and 10% had CNS involvement. CR was achieved in 86% by day 28. MRD negativity was documented in 76% post-induction and 88% post-consolidation. At 5 years, OS, DFS, and EFS were 79%, 68%, and 59%, respectively. Subgroup analysis revealed no significant differences in survival by immunophenotype, risk category, or age group. Common toxicities during induction included febrile neutropenia (40%), infection (35%), and thrombosis (12%). PEG-asparaginase hypersensitivity occurred in 29.5% during consolidation. Multivariate analysis identified CNS involvement (HR 3.81; p = 0.013), post-consolidation MRD positivity (HR 4.58; p < 0.001), and high BMI (>25; HR 3.18; p = 0.002) as independent predictors of adverse outcomes. Conclusions The AYA-15 protocol is effective and well-tolerated in AYA patients with Ph– ALL in a Middle Eastern real-world setting. High CR and MRD clearance rates translated into long-term survival comparable to Western trials. CNS involvement, persistent MRD, and elevated BMI were adverse prognostic factors, supporting the need for risk-adapted strategies. These findings validate the use of pediatric-inspired regimens in non-Western AYA populations and underscore the importance of MRD-guided therapy.