Abstract Background: Therapy-related acute lymphoblastic leukemia (t-ALL) is a rare and aggressive subtype of ALL that arises secondary to cytotoxic therapies for prior malignancies. While t-ALL exhibits distinct adverse cytogenetic features and a worse clinical profile compared to de novo ALL, its comparative survival outcomes remain unclear. Objective: To systematically evaluate and compare survival outcomes between adults with t-ALL and those with de novo ALL. Methods: A systematic review and meta-analysis were conducted in accordance with PRISMA guidelines. Multiple databases were searched up to December 31, 2024. Eligible studies included adult patients (≥18 years) diagnosed with t-ALL or de novo ALL with reported survival outcomes. The pooled hazard ratio (HR) for mortality was estimated using Doi's Quality Effects model, incorporating study quality via the MASTER scale. Results: A total of 169,237 patients across 27 studies were included in the systematic review, including 1,827 patients with t-ALL. Of these, 9 studies (30,527 patients) were eligible for meta-analysis. The pooled HR for overall mortality in t-ALL compared to de novo ALL was 1.07 (95% CI: 0.94–1.23; p = 0.29), indicating no statistically significant difference. Descriptive analysis showed that B-cell lineage was predominant in t-ALL cases (80–100%), while T-cell lineage accounted for 0–20%. t-ALL patients also had higher frequencies of poor-risk cytogenetics, TP53 mutations (38% vs. 10%), and complex karyotypes (5.8–11.1%). Complete remission rates and median overall survival were lower in t-ALL, with a trend toward inferior outcomes that was not statistically significant. Moderate heterogeneity was observed (I² = 50.5%), and publication bias was detected. Sensitivity analyses confirmed the robustness of the pooled estimate. Conclusion: Despite its distinct adverse genetic profile, t-ALL demonstrates comparable overall survival to de novo ALL, particularly in patients receiving allogeneic hematopoietic cell transplantation. These findings underscore the importance of early molecular profiling and aggressive treatment strategies to improve outcomes in this high-risk group. Keywords: therapy-related acute lymphoblastic leukemia, de novo ALL, systematic review, meta-analysis,
Khalid et al. (Mon,) studied this question.